Fused 1,4-dihydrodioxin derivatives as inhibitors of heat shock transcription factor 1

ABSTRACT

The present invention relates to compounds of formula I wherein A 1 , A 2  R 4  and Q are as defined herein. The compounds of the present invention are inhibitors of heat shock factor 1 (HSF1). In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.

INTRODUCTION

The present invention relates to novel compounds that act as inhibitorsof heat shock factor 1 (HSF1) activity. The present invention furtherrelates to processes for preparing the compounds defined herein, topharmaceutical compositions comprising them, and to their use in thetreatment of HSF1-mediated conditions or diseases (such as cancer,autoimmune diseases and viral diseases).

BACKGROUND OF THE INVENTION

Cancer is caused by uncontrolled and unregulated cellular proliferation.Precisely what causes a cell to become malignant and proliferate in anuncontrolled and unregulated manner has been the focus of intenseresearch over recent decades. This research has led to theidentification of a number of molecular targets associated with keymetabolic pathways that are known to be associated with malignancy.

Heat shock factor 1 (HSF1) is one such target molecule. HSF1 is themaster regulator of the heat shock response, in which multiple genes areinduced in response to temperature increase and other stresses. Atnon-shock temperatures in humans and other vertebrates, HSF1 is producedconstitutively, but is inactive and bound by protein HSP90. At anelevated temperature, HSF1 is released by HSP90, moves from thecytoplasm to the nucleus, and trimerizes. This active HSF1 form binds tosequences called heat shock elements (HSE) in DNA and activatestranscription of heat shock genes by RNA polymerase II. The HSE has aconsensus sequence of three repeats of NGAAN and is present in thepromoter regions of the HSP90, HSP70 and HSP27 genes. During cessationof the heat shock response, HSF1 is phosphorylated by mitogen-activatedprotein kinases (MAPKs) and glycogen synthase kinase 3 (GSK3) andreturns to an inactive state. The biochemistry of HSFI is described inmore detail in, inter alia, Chu et al. 1996 J. Biol. Chem.271:30847-30857 and Huang et al. 1997 J. Biol. Chem. 272:26009-26016.

HSF1 also interacts with additional factors. For example, HSF1 binds toDNA-dependent protein kinase (DNA-PK), which is involved in DNA repair.HSF1 is also target of mitogen-activated protein kinases, and itsactivity is down-regulated when the RAS signaling cascade is active.

Additional heat shock factor proteins in humans include HSF2, HSF3, andHSF4. HSF 1, HSF2, and HSF3 are all positive regulators of heat shockgene expression, while HSF4 is a negative regulator. HSF1, HSF2 and HSF4play a role in transcriptional control of other heat shock proteins. Thevarious HSF proteins share about 40% sequence identity.

HSF1 activity has been implicated in several diseases, including cancer,and autoimmune, and viral diseases. HSF1 and other heat shock proteins(whose expression is increased by HSF1) are over-expressed in, or haveotherwise been implicated in, breast, endometrial, fibrosarcoma,gastric, kidney, liver, lung, lymphoma, neuroectodermal, neuroblastoma,Ewing's sarcoma, prostate, skin, squamous cell, and testicular cancers,leukemia (e.g., promyelocytic leukemia), and Hodgkin's disease.

Accordingly, there is need for pharmacologically active agents that arecapable of inhibiting HSF1. Such agents are potentially usefulchemotherapeutic agents for the treatment of diseases or conditions inwhich HSF1 activity is mediated.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound, or apharmaceutically acceptable salt or solvate thereof, as defined herein.

In another aspect, the present invention provides a pharmaceuticalcomposition which comprises a compound as defined herein, or apharmaceutically acceptable salt or solvate thereof, and one or morepharmaceutically acceptable excipients.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in therapy.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the treatmentof HSF1-mediated conditions or diseases (for example, cancer, autoimmunediseases or viral diseases).

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the treatmentof a proliferative condition.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the treatmentof cancer. In a particular embodiment, the cancer is a human cancer.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the productionof a HSF1 inhibitory effect.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in treatment ofHSF1-mediated conditions or diseases (for example, cancer, autoimmunediseases or viral diseases).

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in the treatment ofa proliferative condition.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in the treatment ofcancer. Suitably, the medicament is for use in the treatment of humancancers.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in the production ofa HSF1 inhibitory effect.

In another aspect, the present invention provides a method of inhibitingHSF1 in vitro or in vivo, said method comprising contacting a cell withan effective amount of a compound as defined herein, or apharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of inhibitingcell proliferation in vitro or in vivo, said method comprisingcontacting a cell with an effective amount of a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of treating aHSF1-mediated condition or disease (for example, cancer, autoimmunediseases or viral diseases), in a patient in need of such treatment,said method comprising administering to said patient a therapeuticallyeffective amount of a compound as defined herein, or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical composition asdefined herein.

In another aspect, the present invention provides a method of treating aproliferative disorder in a patient in need of such treatment, saidmethod comprising administering to said patient a therapeuticallyeffective amount of a compound as defined herein, or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical composition asdefined herein.

In another aspect, the present invention provides a method of treatingcancer in a patient in need of such treatment, said method comprisingadministering to said patient a therapeutically effective amount of acompound as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition as defined herein.

The present invention further provides a method of synthesising acompound as defined herein, or a pharmaceutically acceptable salt orsolvate thereof.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof,obtainable by, or obtained by, or directly obtained by a method ofsynthesis as defined herein.

In another aspect, the present invention provides novel intermediatesdefined herein which are suitable for use in any one of the syntheticmethods set out herein.

Preferred, suitable, and optional features of any one particular aspectof the present invention are also preferred, suitable, and optionalfeatures of any other aspect.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the following meanings set out below.

It is to be appreciated that references to “treating” or “treatment”include prophylaxis as well as the alleviation of established symptomsof a condition. “Treating” or “treatment” of a state, disorder orcondition therefore includes: (1) preventing or delaying the appearanceof clinical symptoms of the state, disorder or condition developing in ahuman that may be afflicted with or predisposed to the state, disorderor condition but does not yet experience or display clinical orsubclinical symptoms of the state, disorder or condition, (2) inhibitingthe state, disorder or condition, i.e., arresting, reducing or delayingthe development of the disease or a relapse thereof (in case ofmaintenance treatment) or at least one clinical or subclinical symptomthereof, or (3) relieving or attenuating the disease, i.e., causingregression of the state, disorder or condition or at least one of itsclinical or subclinical symptoms.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups. References to individual alkyl groups suchas “propyl” are specific for the straight chain version only andreferences to individual branched chain alkyl groups such as “isopropyl”are specific for the branched chain version only. For example,“(1-6C)alkyl” includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl andt-butyl. A similar convention applies to other radicals, for example“phenyl(1-6C)alkyl” includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyland 2-phenylethyl.

The term “(m-nC)” or “(m-nC) group” used alone or as a prefix, refers toany group having m to n carbon atoms.

“(3-8C)cycloalkyl” means a hydrocarbon ring containing from 3 to 8carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or bicycle[2.2.2]octane, bicycle[2.1.1]hexane,bicycle[1.1.1]pentane and bicyclo[2.2.1]heptyl.

The term “(1-8C)heteroalkyl” refers to an alkyl chain comprising 1-8carbon atoms which additionally comprises one, two or three heteroatomspresent within the alkyl chain which are selected from the groupconsisting of N, O, or S.

The term “halo” refers to fluoro, chloro, bromo and iodo.

The term “haloalkyl” or “haloalkoxy” is used herein to refer to an alkylor alkoxy group respectively in which one or more hydrogen atoms havebeen replaced by halogen (e.g. fluorine) atoms. Examples of haloalkyland haloalkoxy groups include fluoroalkyl and fluoroalkoxy groups suchas —CHF₂, —CH₂CF₃, or perfluoroalkyl/alkoxy groups such as —CF₃, —CF₂CF₃or —OCF₃.

The term “carbocyclyl”, “carbocyclic” or “carbocycle” means anon-aromatic saturated or partially saturated monocyclic, or a fused,bridged, or spiro bicyclic carbocyclic ring system(s). Monocycliccarbocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ringatoms. Bicyclic carbocycles contain from 7 to 17 carbon atoms in therings, suitably 7 to 12 carbon atoms, in the rings. Bicyclic carbocyclicrings may be fused, spiro, or bridged ring systems.

The term “heterocyclyl”, “heterocyclic” or “heterocycle” means anon-aromatic saturated or partially saturated monocyclic, fused,bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclicheterocyclic rings contain from about 3 to 12 (suitably from 3 to 7)ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selectedfrom nitrogen, oxygen or sulfur in the ring. Bicyclic heterocyclescontain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in thering. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridgedring systems. Examples of heterocyclic groups include cyclic ethers suchas oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substitutedcyclic ethers. Heterocycles containing nitrogen include, for example,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl,tetrahydropyrazolyl, and the like. Typical sulfur containingheterocycles include tetrahydrothienyl, dihydro-1,3-dithiol,tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocyclesinclude dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl,tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl,tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl,tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl,octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocyclescontaining sulfur, the oxidized sulfur heterocycles containing SO or SO₂groups are also included. Examples include the sulfoxide and sulfoneforms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene1,1-dioxide and thiomorpholinyl 1,1-dioxide. A suitable value for aheterocyclyl group which bears 1 or 2 oxo (═O) or thioxo (═S)substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl,2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.Particular heterocyclyl groups are saturated monocyclic 3 to 7 memberedheterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen,oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl,tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl orhomopiperazinyl. As the skilled person would appreciate, any heterocyclemay be linked to another group via any suitable atom, such as via acarbon or nitrogen atom. However, reference herein to piperidino ormorpholino refers to a piperidin-1-yl or morpholin-4-yl ring that islinked via the ring nitrogen. Suitably, the term “heterocyclyl”,“heterocyclic” or “heterocycle” will refer to 4, 5, 6 or 7 memberedmonocyclic rings as defined above.

By “bridged ring systems” is meant ring systems in which two rings sharemore than two atoms, see for example Advanced Organic Chemistry, byJerry March, 4^(th) Edition, Wiley Interscience, pages 131-133, 1992.Examples of bridged heterocyclyl ring systems include,aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane,aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.

By “spiro bi-cyclic ring systems” we mean that the two ring systemsshare one common spiro carbon atom, i.e. the heterocyclic ring is linkedto a further carbocyclic or heterocyclic ring through a single commonspiro carbon atom. Examples of spiro ring systems include6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane,2-azaspiro[3.3]heptanes and 2-oxa-6-azaspiro[3.3]heptanes.

“Heterocyclyl(m-nC)alkyl” means a heterocyclyl group covalently attachedto a (m-nC)alkylene group, both of which are defined herein.

The term “heteroaryl” or “heteroaromatic” means an aromatic mono-, bi-,or polycyclic ring incorporating one or more (for example 1-4,particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen orsulfur. Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to twelve ring members, and more usually from fiveto ten ring members. The heteroaryl group can be, for example, a 5- or6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, forexample a bicyclic structure formed from fused five and six memberedrings or two fused six membered rings. Each ring may contain up to aboutfour heteroatoms typically selected from nitrogen, sulfur and oxygen.Typically the heteroaryl ring will contain up to 3 heteroatoms, moreusually up to 2, for example a single heteroatom. In one embodiment, theheteroaryl ring contains at least one ring nitrogen atom. The nitrogenatoms in the heteroaryl rings can be basic, as in the case of animidazole or pyridine, or essentially non-basic as in the case of anindole or pyrrole nitrogen. In general the number of basic nitrogenatoms present in the heteroaryl group, including any amino groupsubstituents of the ring, will be less than five. Suitably, the term“heteroaryl” or “heteroaromatic” will refer to 5 or 6 memberedmonocyclic heteroaryl rings as defined above.

Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl,isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl,naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl,pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl,5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl,4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl,imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. “Heteroaryl”also covers partially aromatic bi- or polycyclic ring systems wherein atleast one ring is an aromatic ring and one or more of the other ring(s)is a non-aromatic, saturated or partially saturated ring, provided atleast one ring contains one or more heteroatoms selected from nitrogen,oxygen or sulfur. Examples of partially aromatic heteroaryl groupsinclude for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl,2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl,dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl,2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl,indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl,1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

Examples of five membered heteroaryl groups include but are not limitedto pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl,oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, triazolyl and tetrazolyl groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

A bicyclic heteroaryl group may be, for example, a group selected from:

-   -   a) a benzene ring fused to a 5- or 6-membered ring containing 1,        2 or 3 ring heteroatoms;    -   b) a pyridine ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms;    -   c) a pyrimidine ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   d) a pyrrole ring fused to a 5- or 6-membered ring containing 1,        2 or 3 ring heteroatoms;    -   e) a pyrazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   f) a pyrazine ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   g) an imidazole ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   h) an oxazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   i) an isoxazole ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   j) a thiazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   k) an isothiazole ring fused to a 5- or 6-membered ring        containing 1 or 2 ring heteroatoms;    -   l) a thiophene ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms;    -   m) a furan ring fused to a 5- or 6-membered ring containing 1, 2        or 3 ring heteroatoms;    -   n) a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic        ring containing 1, 2 or 3 ring heteroatoms; and    -   o) a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic        ring containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl,indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl(e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine,and pyrazolopyridinyl groups.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinolinyl,isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl,chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl,benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, naphthyridinyl and pteridinyl groups.

“Heteroaryl(m-nC)alkyl” means a heteroaryl group covalently attached toa (m-nC)alkylene group, both of which are defined herein. Examples ofheteroaralkyl groups include pyridin-3-ylmethyl,3-(benzofuran-2-yl)propyl, and the like.

The term “aryl” means a cyclic or polycyclic aromatic ring having from 5to 12 carbon atoms. The term aryl includes both monovalent species anddivalent species. Examples of aryl groups include, but are not limitedto, phenyl, biphenyl, naphthyl and the like. In particular embodiment,an aryl is phenyl or naphthyl, especially phenyl.

The term “aryl(m-nC)alkyl” means an aryl group covalently attached to a(m-nC)alkylene group, both of which are defined herein. Examples ofaryl-(m-nC)alkyl groups include benzyl, phenylethyl, and the like.

This specification also makes use of several composite terms to describegroups comprising more than one functionality. Such terms will beunderstood by a person skilled in the art. For exampleheterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted byheterocyclyl.

The term “optionally substituted” refers to either groups, structures,or molecules that are substituted and those that are not substituted.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

The phrase “compound of the invention” means those compounds which aredisclosed herein, both generically and specifically.

Compounds of the Invention

In one aspect, the present invention provides a compound of formula Ishown below:

wherein:A₁ is selected from N or CR₁, A₂ is selected from N or CR₂, with theproviso that only one of A₁ or A₂ can be N;R₁ and R₂ are each independently selected from hydrogen, fluoro, chloro,cyano, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy;R₄ is selected from hydrogen, fluoro, chloro, bromo, iodo, CF₃, OCF₃,cyano, NO₂, (1-4C)alkyl, (1-4C)alkoxy, or a group of the formula:

W—X—Y—Z

wherein

-   -   W is absent or (1-3C)alkylene;    -   X is —O— or —N(R^(a))—, wherein R^(a) is selected from hydrogen        or (1-2C)alkyl;    -   Y is absent or a (1-3C)alkylene;    -   Z is hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;

and wherein any alkylene, alkyl or cycloalkyl group present in a R₄substituent group is optionally further substituted by one or moresubstituent groups independently selected from halo, hydroxy,NR^(b)R^(c), (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy, andwherein R^(b) and R^(c) are each independently selected from hydrogen or(1-3C)alkyl; Q is selected from a group of formula II:

wherein

-   -   A_(4a) and A_(4b) are each independently selected from N or CR₉,        wherein each R₉ present is independently selected from hydrogen,        halo, cyano, nitro, hydroxy, NR^(d)R^(e), (1-3C)alkyl,        (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6 membered        heterocyclyl; wherein R^(d) and R^(e) are each independently        selected from hydrogen or (1-3C)alkyl; and wherein any        (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6        membered heterocyclyl group present in a R₉ substituent group is        optionally substituted by one or more substituents selected from        halo, cyano, nitro, hydroxy, NR^(f)R^(g) or (1-3C)alkoxy,        wherein R^(f) and R^(g) are each independently selected from        hydrogen or (1-3C)alkyl;    -   A_(4c) is N or CR₁₀;    -   R₁₀ is selected from hydrogen, halo, amino, cyano, nitro,        hydroxy or a group

W¹—X¹—Y¹—X⁴—Z¹

-   -   -   wherein            -   W¹ is absent or a linker group of the formula                —[CR^(h)R^(i)]_(p)— in which p is an integer selected                from 1, 2, 3 or 4, and R^(h) and R^(i) are each                independently selected from hydrogen or (1-2C)alkyl;            -   X¹ is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—,                —CH(OR^(j))—, —N(R^(j))—, —N(R^(j))—C(O)—,            -   —N(R^(j))—C(O)O—, —C(O)—N(R^(j))—,                —N(R^(j))C(O)N(R^(j))—, —S—, —SO—, —SO₂—,                —S(O)₂N(R^(j))—, or —N(R^(j))SO₂— wherein R^(j) is                selected from hydrogen or methyl;            -   Y¹ is absent or a linker group of the formula                —[CR^(k)R^(l)]_(q)— in which q is an integer selected                from 1, 2, 3 or 4, and R^(k) and R^(l) are each                independently selected from hydrogen or (1-2C)alkyl;            -   X⁴ is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—,                —CH(OR^(j))—, —N(R^(j))—, —N(R^(j))—C(O)—,            -   —N(R^(j))—C(O)O—, —C(O)—N(R^(i))—,                —N(R^(j))C(O)N(R^(j))—, —S—, —SO—, —SO₂—,                —S(O)₂N(R^(j))—, or —N(R^(j))SO₂— wherein R^(i) is                selected from hydrogen or methyl; and            -   Z¹ is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl,                (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or                heterocyclyl;                -   and wherein Z¹ is optionally further substituted by                    one or more substituent groups independently                    selected from oxo, halo, cyano, nitro, hydroxy,                    caboxy, NR^(m)R^(n), (1-4C)alkoxy, (1-4C)alkyl,                    (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl,                    (1-4C)alkanoyl, (1-4C)alkylsulphonyl, aryl, aryloxy,                    heterocyclyl, heterocyclyloxy,                    heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryloxy,                    heteroaryl-(1-2C)alkyl, C(O)NR^(m)R^(n),                    NR^(m)C(O)R^(n), NR^(m)S(O)₂R^(n) and                    S(O)₂NR^(m)R^(n);                -   wherein R^(m) and R^(n) are each independently                    selected from hydrogen, (1-4C)alkyl or                    (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or                    R^(m) and R^(n) can be linked such that, together                    with the nitrogen atom to which they are attached,                    they form a 4-6 membered heterocyclic ring;                -   and wherein any alkyl, aryl, heterocyclyl or                    heteroaryl group present in a substituent group on                    Z¹ is optionally further substituted by halo, cyano,                    nitro, hydroxy, caboxy, NR^(c)R^(p), (1-2C)alkoxy,                    or (1-2C)alkyl;                -   wherein R^(o) and R^(p) are selected from hydrogen                    or (1-2C)alkyl;        -   with the proviso that R₁₀ is only hydrogen or t-butyl when            at least one of A_(4a) and A_(4b) is N or CR₉ in which R₉ is            a substituent as defined above other than hydrogen;            or Q is a group of formula III:

wherein

-   -   A₅ is selected from N or CR₅, where R₅ is selected from        hydrogen, halo, cyano, nitro, hydroxy, NR^(q)R^(u), (1-3C)alkyl,        (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6 membered        heterocyclyl; wherein R^(q) and R^(u) are each independently        selected from hydrogen or (1-3C)alkyl, and wherein any        (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6        membered heterocyclyl group present in a R₅ substituent group is        optionally substituted by one or more substitutents selected        from halo, cyano, nitro, hydroxy, NR^(v)R^(w), or (1-3C)alkoxy,        wherein R^(v) and R^(w) are each independently selected from        hydrogen or (1-3C)alkyl;    -   Ring A is:        -   a fused phenyl ring;        -   a fused 5 or 6 membered carbocyclic ring;        -   a fused 5 or 6 membered heteroaryl ring comprising one or            two heteroatoms independently from N, S or O; or        -   a fused 5, 6 or 7-membered heterocyclic ring comprising one            or two heteroatoms independently from N, S or O;    -   A₆ is selected from N, O, S, S(O), S(O)₂, CR₆, C(R₆)₂, NR₆₀,        where R₆ is selected from hydrogen, oxo, fluoro, chloro,        (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or (1-2C)haloalkyl        and R₆₀ is hydrogen, O⁻, (1-6C)alkyl, —C(O)—R₆₁, —C(O)O—R₆₁, or        —C(O)N(R₆₂)R₆₁, wherein R₆₁ is selected from hydrogen,        (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heteroaryl or heterocyclyl        and R₆₂ is selected from hydrogen or (1-3C)alkyl;    -   A₇ is selected from N, O, CR₇, S, S(O), S(O)₂, C(R₇)₂, NR₇₀,        where R₇₀ is hydrogen, O⁻, (1-6C)alkyl, —C(O)—R₇₁, —C(O)O—R₇₁,        or —C(O)N(R₇₂)R₇₁, wherein R₇₁ is selected from hydrogen,        (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heteroaryl or heterocyclyl        and R₇₂ is selected from hydrogen or (1-3C)alkyl; m is 0, 1 or        2;    -   R₇ and R₁₁ are each independently halo, cyano, oxo, or a group

W²—X²—Y²—X³—Z²

-   -   -   wherein            -   W² is absent or a linker group of the formula                —[CR^(x)R^(y)]_(r)— in which r is an integer selected                from 1, 2, 3 or 4, and R^(x) and R^(y) are each                independently selected from hydrogen or (1-2C)alkyl;            -   X² is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—,                —CH(OR^(z))—, —N(R^(z))—, —N(R^(z))—C(O)—,                —N(R²)—C(O)O—, —C(O)—N(R^(z))—, —N(R^(z))C(O)N(R^(z))—,                —S—, —SO—, —SO₂—, —S(O)₂N(R^(z))—, or —N(R^(z))SO₂,                wherein R^(z) is selected from hydrogen or methyl;            -   Y² is absent or a linker group of the formula                —[CR^(aa)R^(bb)]_(s)— in which s is an integer selected                from 1, 2, 3 or 4, and R^(aa) and R^(bb) are each                independently selected from hydrogen or (1-2C)alkyl;            -   X³ is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—,                —CH(OR^(cc))—, —N(R^(cc)), —N(R^(cc))—C(O)—,                —N(R^(cc))—C(O)O—, —C(O)—N(R^(cc))—,                —N(R^(cc))C(O)N(R^(cc))—, —S—, —SO—, —SO₂—,                —S(O)₂N(R^(cc))—, or —N(R^(cc))SO₂, wherein R is                selected from hydrogen or methyl; and            -   Z² is hydrogen, (1-6C)alkyl, (2-6C)alkenyl,                (2-6C)alkynyl, aryl, (3-6C)cycloalkyl,                (3-6C)cycloalkenyl, heteroaryl, or heterocyclyl, and                wherein Z² is optionally further substituted by one or                more substituent groups independently selected from oxo,                halo, cyano, nitro, hydroxy, caboxy, NR^(dd)R^(ee),                (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl,                (3-8C)cycloalkyl-(1-3C)alkyl, (1-4C)alkanoyl,                (1-4C)alkylsulphonyl, aryl, aryloxy, heterocyclyl,                heterocyclyloxy, heterocyclyl-(1-2C)alkyl, heteroaryl,                heteroaryloxy, heteroaryl-(1-2C)alkyl,                C(O)NR^(dd)R^(ee), NR^(dd)C(O)R^(ee), NR^(dd)SO₂R^(ee)                and SO₂NR^(dd)R^(ee); wherein R^(dd) and R^(ee) are each                independently selected from hydrogen, (1-4C)alkyl,                (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or                R^(dd) and R^(ee) can be linked such that, together with                the nitrogen atom to which they are attached, they form                a 4-6 membered heterocyclic ring;            -   and wherein any alkyl, aryl, heterocyclyl or heteroaryl                group present in a substituent group on Z² is optionally                further substituted by halo, cyano, nitro, hydroxy,                caboxy, NR^(ff)R^(gg), (1-2C)alkoxy, or (1-2C)alkyl;                wherein R^(ff) and R^(gg) are selected from hydrogen or                (1-2C)alkyl;

    -   with the proviso that when R₇ is hydrogen (i.e. when W², X², Y²,        and X³ are absent and Z² is hydrogen) then ring A is not a fused        dioxane ring;

    -   or a pharmaceutically acceptable salt or solvate thereof.

In an embodiment, when A₁ and A₂ are both CH and R₄ is H, Q is notpyrid-4-yl, i.e.

As indicated above, R₁₀ is only hydrogen or t-butyl when at least one ofA_(4a) and A_(4b) is N or CR₉ in which R₉ is a substituent as definedherein other than hydrogen (i.e. R₉ is selected from halo, cyano, nitro,hydroxy, NR^(d)R^(e), (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-memberedheteroaryl, or 5 or 6 membered heterocyclyl; wherein R^(d) and R^(e) areeach independently selected from hydrogen or (1-3C)alkyl; and whereinany (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6membered heterocyclyl group present in a R₉ substituent group isoptionally substituted by halo, cyano, nitro, hydroxy, NR^(f)R^(g) or(1-3C)alkoxy, wherein R^(f) and R^(g) are each independently selectedfrom hydrogen or (1-3C)alkyl).

The ring A fused ring systems shown in Formula III are made up of twocarbon atoms from adjacent fused ring, the atoms A₆ and A₇ and eitherone, two or three additional ring atoms that link A₇ to the fused ring(depending on whether ring A is a fused 5, 6 or 7 membered ringrespectively). For the avoidance of doubt, when m is 1 or 2 then eachR₁₁ group present resides on the one, two or three additional ring atomsthat are present in Ring A (i.e. they are not present on atoms A₆ andA₇).

Particular compounds of the invention include, for example, compounds ofthe formula I, or pharmaceutically acceptable salts or solvates thereof,wherein, unless otherwise stated, each of A₁, A₂, R₁, R₂, R₄, Q, A_(4a),A_(4b), A_(4c), R₁₀, A₅, ring A, A₆, A₇, R₇, m and R₁₁ has any of themeanings defined hereinbefore or in any one of paragraphs (1) to (42)hereinafter:—

-   (1) A₁ is N;-   (2) A₁ is CR₁;-   (3) R₁ is selected from hydrogen, fluoro, chloro, cyano, methyl,    methoxy, —CF₃ or —OCF₃;-   (4) R₁ is selected from hydrogen or fluoro;-   (5) R₁ is hydrogen;-   (6) A₂ is N;-   (7) A₂ is CR₂;-   (8) R₂ is selected from hydrogen, fluoro, chloro, cyano, methyl,    methoxy, —CF₃ or —OCF₃;-   (9) R₂ is selected from hydrogen or fluoro;-   (10) R₂ is hydrogen;-   (11) R₄ is selected from fluoro, chloro, bromo, iodo, CF₃, OCF₃,    cyano, NO₂, (1-4C)alkyl, (1-4C)alkoxy, or a group of the formula:

W—X—Y—Z

-   -   wherein        -   W is absent or (1-3C)alkylene;        -   X is —O— or —N(R^(a))—, wherein R^(a) is selected from            hydrogen or (1-2C)alkyl;        -   Y is absent or a (1-3C)alkylene;        -   Z is hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;        -   and wherein any alkylene, alkyl or cycloalkyl group present            in a R₄ substituent group is optionally further substituted            by one or more substituent groups independently selected            from halo, hydroxy, NR^(b)R^(c), (1-2C)alkoxy,            (1-2C)haloalkyl or (1-2C)haloalkoxy, and wherein R^(b) and            R^(c) are each independently selected from hydrogen or            methyl;

-   (12) R₄ is selected from fluoro, chloro, bromo, iodo, CF₃, OCF₃,    cyano, NO₂, (1-4C)alkyl, (1-4C)alkoxy, or a group of the formula:

W—X—Y—Z

-   -   wherein        -   W is absent or (1-3C)alkylene;        -   X is —O— or —N(R^(a))—, wherein R^(a) is selected from            hydrogen or (1-2C)alkyl;        -   Y is absent or a (1-2C)alkylene;        -   Z is hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;        -   and wherein any alkylene, alkyl or cycloalkyl group present            in a R₄ substituent group is optionally further substituted            by one or more substituent groups independently selected            from halo, hydroxy, NR^(b)R^(c), (1-2C)alkoxy,            (1-2C)haloalkyl or (1-2C)haloalkoxy, and wherein R^(b) and            R^(c) are each independently selected from hydrogen or            methyl;

-   (13) R₄ is selected from fluoro, chloro, bromo, iodo, CF₃, OCF₃,    cyano, (1-2C)alkyl, (1-2C)alkoxy, or a group of the formula:

W—X—Y—Z

-   -   wherein        -   W is absent or (1-2C)alkylene;        -   X is —O— or —N(R^(a))—, wherein R^(a) is selected from            hydrogen or (1-2C)alkyl;        -   Y is absent or a (1-2C)alkylene;        -   Z is hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;    -   and wherein any alkylene, alkyl or cycloalkyl group present in a        R₄ substituent group is optionally further substituted by one or        more substituent groups independently selected from halo,        hydroxy, NR^(b)R^(c), (1-2C)alkoxy, or (1-2C)haloalkyl; and        wherein R^(b) and R^(c) are each independently selected from        hydrogen or methyl;

-   (14) R₄ is selected from fluoro, chloro, bromo, CF₃, OCF₃, cyano,    (1-2C)alkyl, (1-2C)alkoxy, or a group of the formula:

W—X—Y—Z

-   -   wherein        -   W is absent or methylene;        -   X is —O— or —N(R^(a))—, wherein R^(a) is selected from            hydrogen or (1-2C)alkyl;        -   Y is absent or methylene;        -   Z is hydrogen or (1-6C)alkyl;    -   and wherein any alkylene or alkyl group present in a R₄        substituent group is optionally further substituted by one or        more substituent groups independently selected from halo,        hydroxy, NR^(b)R^(c) or (1-2C)alkoxy, and wherein R^(b) and        R^(c) are each independently selected from hydrogen or methyl;

-   (15) R₄ is selected from fluoro, chloro, bromo, CF₃, cyano,    (1-2C)alkyl, or a group of the formula:

W—X—Y—Z

-   -   wherein        -   W is absent or methylene;        -   X is —O— or —N(R^(a))—, wherein R^(a) is selected from            hydrogen or (1-2C)alkyl;        -   Y is absent;        -   Z is hydrogen or (1-6C)alkyl;    -   and wherein any alkylene or alkyl group present in a R₄        substituent group is optionally further substituted by one or        more substituent groups independently selected from halo,        hydroxy, NR^(b)R^(c) or (1-2C)alkoxy, and wherein R^(b) and        R^(c) are each independently selected from hydrogen or methyl;

-   (16) R₄ is selected from fluoro, chloro or (1-2C)alkyl;

-   (17) R₄ is selected from fluoro, chloro or methyl;

-   (18) R₄ is selected from hydrogen, fluoro, chloro, bromo, iodo, CF₃,    OCF₃, cyano, NO₂, (1-4C)alkyl, (1-4C)alkoxy, or a group of the    formula:

W—X—Y—Z

-   -   wherein        -   W is absent or (1-3C)alkylene;        -   X is —O— or —N(R^(a))—, wherein R^(a) is selected from            hydrogen or (1-2C)alkyl;        -   Y is absent or a (1-3C)alkylene;        -   Z is hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;    -   and wherein any alkylene, alkyl or cycloalkyl group present in a        R₄ substituent group is optionally further substituted by one or        more substituent groups independently selected from halo,        hydroxy, NR^(b)R^(c), (1-2C)alkoxy, (1-2C)haloalkyl or        (1-2C)haloalkoxy, and wherein R^(b) and R^(c) are each        independently selected from hydrogen or methyl;

-   (19) R₄ is selected from hydrogen, fluoro, chloro, bromo, iodo, CF₃,    OCF₃, cyano, NO₂, (1-4C)alkyl, (1-4C)alkoxy, or a group of the    formula:

W—X—Y—Z

-   -   wherein        -   W is absent or (1-2C)alkylene;        -   X is —O— or —N(R^(a))—, wherein R^(a) is selected from            hydrogen or (1-2C)alkyl;        -   Y is absent or a (1-2C)alkylene;        -   Z is hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;    -   and wherein any alkylene, alkyl or cycloalkyl group present in a        R₄ substituent group is optionally further substituted by one or        more substituent groups independently selected from halo,        hydroxy, NR^(b)R^(c), (1-2C)alkoxy, (1-2C)haloalkyl or        (1-2C)haloalkoxy, and wherein R^(b) and R^(c) are each        independently selected from hydrogen or methyl;

-   (20) R₄ is selected from hydrogen, fluoro, chloro, bromo, iodo, CF₃,    OCF₃, cyano, (1-2C)alkyl, (1-2C)alkoxy, or a group of the formula:

W—X—Y—Z

-   -   wherein        -   W is absent or (1-2C)alkylene;        -   X is —O— or —N(R^(a))—, wherein R^(a) is selected from            hydrogen or (1-2C)alkyl;        -   Y is absent or a (1-2C)alkylene;        -   Z is hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;    -   and wherein any alkylene, alkyl or cycloalkyl group present in a        R₄ substituent group is optionally further substituted by one or        more substituent groups independently selected from halo,        hydroxy, NR^(b)R^(c), (1-2C)alkoxy, or (1-2C)haloalkyl; and        wherein R^(b) and R^(c) are each independently selected from        hydrogen or methyl;

-   (21) R₄ is selected from hydrogen, fluoro, chloro, bromo, CF₃, OCF₃,    cyano, (1-2C)alkyl, (1-2C)alkoxy, or a group of the formula:

W—X—Y—Z

-   -   wherein        -   W is absent or methylene;        -   X is —O— or —N(R^(a))—, wherein R^(a) is selected from            hydrogen or (1-2C)alkyl;        -   Y is absent or methylene;        -   Z is hydrogen or (1-6C)alkyl;    -   and wherein any alkylene or alkyl group present in a R₄        substituent group is optionally further substituted by one or        more substituent groups independently selected from halo,        hydroxy, NR^(b)R^(c) or (1-2C)alkoxy, and wherein R^(b) and        R^(c) are each independently selected from hydrogen or methyl;

-   (22) R₄ is selected from hydrogen, fluoro, chloro, bromo, CF₃,    cyano, (1-2C)alkyl, or a group of the formula:

W—X—Y—Z

-   -   wherein        -   W is absent or methylene;        -   X is —O— or —N(R^(a))—, wherein R^(a) is selected from            hydrogen or (1-2C)alkyl;        -   Y is absent;        -   Z is hydrogen or (1-6C)alkyl;    -   and wherein any alkylene or alkyl group present in a R₄        substituent group is optionally further substituted by one or        more substituent groups independently selected from halo,        hydroxy, NR^(b)R^(c) or (1-2C)alkoxy, and wherein R^(b) and        R^(c) are each independently selected from hydrogen or methyl;

-   (23) Q is selected from a group of formula II:

-   -   wherein    -   A_(4a) and A_(4b) are each independently selected from N or CR₉,        wherein R₉ is selected from hydrogen, halo, cyano, nitro,        hydroxy, NR^(d)R^(e), (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered        heteroaryl, or 5 or 6 membered heterocyclyl; wherein R^(d) and        R^(e) are each independently selected from hydrogen or        (1-3C)alkyl;    -   and wherein any (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered        heteroaryl, or 5 or 6 membered heterocyclyl group present in a        R₉ substituent group is optionally substituted by one or more        substituents selected from halo, cyano, hydroxy, NR^(f)R^(g) or        (1-3C)alkoxy, wherein R^(f) and R^(g) are each independently        selected from hydrogen or (1-2C)alkyl;    -   A₄, is N or CR₁₀;    -   R₁₀ is selected from hydrogen, halo, amino, cyano, nitro,        hydroxy or a group

W¹—X¹—Y¹—X⁴—Z¹

-   -   wherein        -   W¹ is absent or a linker group of the formula            —[CR^(h)R^(i)]_(p)— in which p is an integer selected from 1            or 2, and R^(h) and R^(i) are each independently selected            from hydrogen or methyl;        -   X¹ is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR^(i))—,            —N(R^(j))—, —N(R^(j))—C(O)—, —N(R^(j))—C(O)O—,            —C(O)—N(R^(j))—, —S—, —SO—, —SO₂—, —S(O)₂N(R^(j))—, or            —N(R^(j))SO₂— wherein R^(i) is selected from hydrogen or            methyl;        -   Y¹ is absent or a linker group of the formula            —[CR^(k)R^(l)]_(q)— in which q is an integer selected from            1, 2, 3 or 4, and R^(k) and R^(l) are each independently            selected from hydrogen or (1-2C)alkyl;        -   X⁴ is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR^(i))—,            —N(R^(j))—, —N(R^(j))—C(O)—, —N(R^(j))—C(O)O—,            —C(O)—N(R^(i))—, —S—, —SO—, —SO₂—, —S(O)₂N(R^(i))—, or            —N(R^(j))SO₂— wherein R^(j) is selected from hydrogen or            methyl; and        -   Z¹ is (1-6C)alkyl, aryl, heteroaryl or heterocyclyl;            -   and wherein Z¹ is optionally further substituted by one                or more substituent groups independently selected from                oxo, halo, cyano, hydroxy, caboxy, NR^(m)R^(n),                (1-2C)alkoxy, (1-2C)alkyl, (3-6C)cycloalkyl,                (3-6C)cycloalkyl-(1-2C)alkyl, (1-2C)alkanoyl,                (1-2C)alkylsulphonyl, aryl, aryloxy, heterocyclyl,                heterocyclyloxy, heterocyclyl-(1-2C)alkyl, heteroaryl,                heteroaryloxy, heteroaryl-(1-2C)alkyl, C(O)NR^(m)R^(n),                NR^(m)C(O)R^(n), NR^(m)S(O)₂R^(n) and S(O)₂NR^(m)R^(n);                wherein R^(m) and R^(n) are each independently selected                from hydrogen or (1-4C)alkyl; or R^(m) and R^(n) can be                linked such that, together with the nitrogen atom to                which they are attached, they form a 4-6 membered                heterocyclic ring;            -   and wherein any alkyl, aryl, heterocyclyl or heteroaryl                group present in a substituent group on Z¹ is optionally                further substituted by halo, cyano, hydroxy,                NR^(c)R^(p), (1-2C)alkoxy, or (1-2C)alkyl; wherein R^(o)                and R^(p) are selected from hydrogen or (1-2C)alkyl;    -   or Q is a group of formula III:

-   -   wherein    -   A₅ is selected from N or CR₅, where R₅ is selected from        hydrogen, halo, cyano, hydroxy, NR^(q)R^(u), (1-3C)alkyl,        (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6 membered        heterocyclyl; wherein R^(q) and R^(u) are each independently        selected from hydrogen or (1-3C)alkyl; and wherein any        (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6        membered heterocyclyl group present in a R₅ substituent group is        optionally substituted by one or more substitutents selected        from halo, cyano, nitro, hydroxy, NR^(v)R^(w), or (1-3C)alkoxy,        wherein R^(v) and R^(w) are each independently selected from        hydrogen or (1-3C)alkyl;    -   Ring A is:        -   a fused phenyl ring;        -   a fused 5 or 6 membered carbocyclic ring;        -   a fused 5 or 6 membered heteroaryl ring comprising one or            two        -   heteroatoms independently from N, S or O; or        -   a fused 5, 6 or 7-membered heterocyclic ring comprising one            or two heteroatoms independently from N, S or O;    -   A₆ is selected from N, O, S, S(O)₂, CR₆, C(R₆)₂, NR₆₀, where R₆        is selected from hydrogen, oxo, fluoro, chloro, (1-2C)alkyl,        (1-2C)alkoxy, (1-2C)haloalkoxy or (1-2C)haloalkyl and R₆₀ is        hydrogen, O⁻, (1-6C)alkyl, —C(O)—R₆₁, —C(O)O—R₆₁, or        —C(O)N(R₆₂)R₆₁, wherein R₆₁ is selected from hydrogen,        (1-6C)alkyl, aryl, heteroaryl or heterocyclyl and R₆₂ is        selected from hydrogen or (1-2C)alkyl;    -   A₇ is selected from N, O, CR₇, S, S(O)₂, C(R₇)₂, NR₇₀, where R₇₀        is hydrogen, O⁻, (1-6C)alkyl, —C(O)—R₇₁, —C(O)O—R₇₁, or        —C(O)N(R₂)R₇, wherein R₇₁ is selected from hydrogen,        (1-6C)alkyl, aryl, heteroaryl or heterocyclyl and R₇₂ is        selected from hydrogen or (1-2C)alkyl;    -   m is 0, 1 or 2;    -   R₇ and R₁₁ are each independently halo, cyano, oxo, or a group

W²—X²—Y²—X³—Z²

-   -   -   wherein        -   W² is absent or a linker group of the formula            —[CR^(x)R^(y)]_(r)— in which r is an integer selected from            1, 2, 3 or 4, and R^(x) and R^(y) are each independently            selected from hydrogen or (1-2C)alkyl;        -   X² is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR^(z))—,            —N(R^(z))—, —N(R^(z))—C(O)—, —N(R^(z))—C(O)O—,            —C(O)—N(R^(z))—, —S—, —SO—, —SO₂—, —S(O)₂N(R^(z))—, or            —N(R^(z))SO₂, wherein R^(z) is selected from hydrogen or            methyl;        -   Y² is absent or a linker group of the formula            —[CR^(aa)R^(bb)]_(s)— in which s is an integer selected from            1, 2, 3 or 4, and R^(aa) and R^(bb) are each independently            selected from hydrogen or (1-2C)alkyl;        -   X³ is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR^(cc))—,            —N(R^(cc)), —N(R^(cc))—C(O)—, —N(R^(cc))—C(O)O—,            —C(O)—N(R^(cc))—, —S—, —SO—, —SO₂—, —S(O)₂N(R^(cc))—, or            —N(R^(cc))SO₂, wherein R^(cc) is selected from hydrogen or            methyl; and        -   Z² is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, aryl,            (3-6C)cycloalkyl, heteroaryl, or heterocyclyl,            -   and wherein Z² is optionally further substituted by one                or more substituent groups independently selected from                oxo, halo, cyano, nitro, hydroxy, caboxy, NR^(dd)R^(ee),                (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl,                (1-2C)alkanoyl, (1-2C)alkylsulphonyl, aryl, aryloxy,                heterocyclyl, heterocyclyloxy, heterocyclyl-(1-2C)alkyl,                heteroaryl, heteroaryloxy, heteroaryl-(1-2C)alkyl,                C(O)NR^(dd)R^(ee), NR^(dd)C(O)R^(ee), NR^(dd)SO₂R^(ee)                and SO₂NR^(dd)R^(ee); wherein R^(dd) and R^(ee) are each                independently selected from hydrogen, (1-4C)alkyl,                (3-6C)cycloalkyl; or R^(dd) and R^(ee) can be linked                such that, together with the nitrogen atom to which they                are attached, they form a 4-6 membered heterocyclic                ring;            -   and wherein any alkyl, aryl, heterocyclyl or heteroaryl                group present in a substituent group on Z² is optionally                further substituted by halo, cyano, nitro, hydroxy,                caboxy, NR^(ff)R^(gg), (1-2C)alkoxy, or (1-2C)alkyl;                wherein R^(ff) and R^(gg) are selected from hydrogen or                (1-2C)alkyl;

-   (24) Q is a group of formula II as defined herein;

-   (25) A_(4a) and A_(4b) are each independently selected from N or    CR₉, wherein R₉ is selected from hydrogen, halo, cyano, hydroxy,    NR^(d)R^(e), (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered heteroaryl,    or 5 or 6 membered heterocyclyl; wherein R^(d) and R^(e) are each    independently selected from hydrogen or (1-2C)alkyl;    -   and wherein any (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered        heteroaryl, or 5 or 6 membered heterocyclyl group present in a        R₉ substituent group is optionally substituted by one or more        substituents selected from halo, cyano, hydroxy, NR^(f)R^(g) or        (1-3C)alkoxy, wherein R^(f) and R^(g) are each independently        selected from hydrogen or (1-2C)alkyl;

-   (26) A_(4a) and A_(4b) are each independently selected from N or    CR₉, wherein R₉ is selected from hydrogen, halo, cyano, hydroxy,    NR^(d)R^(e), (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered heteroaryl,    or 5 or 6 membered heterocyclyl; wherein R^(d) and R^(e) are each    independently selected from hydrogen or (1-2C)alkyl;

-   (27) A_(4c) is N;

-   (28) A_(4c) is CR₁₀;

-   (29) R₁₀ is selected from hydrogen, halo, amino, cyano, hydroxy or a    group

W¹—X¹—Y¹—X⁴—Z¹

-   -   wherein    -   W¹ is absent or a linker group of the formula —[CR^(h)R^(i)]_(p)        in which p is an integer selected from 1 or 2, and R^(h) and        R^(i) are hydrogen;    -   X¹ is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R^(j))—,        —N(R^(j))—C(O)—, —N(R^(j))—C(O)O—, —C(O)—N(R^(j))—, —S—, —SO—,        —SO₂—, —S(O)₂N(R^(j))—, or —N(R^(j))SO₂— wherein R^(i) is        selected from hydrogen or methyl;    -   Y¹ is absent or a linker group of the formula        —[CR^(k)R^(l)]_(q)— in which q is an integer selected from 1, 2,        3 or 4, and R^(k) and R^(l) are each independently selected from        hydrogen or methyl;    -   X⁴ is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R^(j))—,        —N(R^(j))—C(O)—, —N(R^(j))—C(O)O—, —C(O)—N(R^(j))—, —S—, —SO—,        —SO₂—, —S(O)₂N(R^(j))—, or —N(R^(j))SO₂— wherein R^(i) is        selected from hydrogen or methyl; and    -   Z¹ is (1-6C)alkyl, aryl, heteroaryl or heterocyclyl;        -   and wherein Z¹ is optionally further substituted by one or            more substituent groups independently selected from oxo,            halo, cyano, hydroxy, caboxy, NR^(m)R^(n), (1-2C)alkoxy,            (1-2C)alkyl, (3-6C)cycloalkyl, (1-2C)alkanoyl,            (1-2C)alkylsulphonyl, aryl, aryloxy, heterocyclyl,            heterocyclyloxy, heterocyclyl-(1-2C)alkyl, heteroaryl,            heteroaryloxy, heteroaryl-(1-2C)alkyl, C(O)NR^(m)R^(n),            NR^(m)C(O)R^(n), NR^(m)S(O)₂R^(n) and S(O)₂NR^(m)R^(n);            wherein R^(m) and R^(n) are each independently selected from            hydrogen or (1-4C)alkyl; or R^(m) and R^(n) can be linked            such that, together with the nitrogen atom to which they are            attached, they form a 4-6 membered heterocyclic ring;        -   and wherein any alkyl, aryl, heterocyclyl or heteroaryl            group present in a substituent group on Z¹ is optionally            further substituted by halo, cyano, hydroxy, NR^(c)R^(p),            (1-2C)alkoxy, or (1-2C)alkyl; wherein R^(o) and R^(p) are            selected from hydrogen or (1-2C)alkyl;

-   (30) R₁₀ is selected from hydrogen, halo, amino, cyano, hydroxy or a    group

W¹—X¹—Y¹—X⁴—Z¹

-   -   wherein        -   W¹ is absent;        -   X¹ is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R^(j))—,            —N(R^(j))—C(O)—, —N(R^(j))—C(O)O—, —C(O)—N(R^(j))—, —S—,            —SO—, —SO₂—, —S(O)₂N(R^(j))—, or —N(R^(j))SO₂— wherein R^(i)            is selected from hydrogen or methyl;        -   Y¹ is absent or a linker group of the formula            —[CR^(k)R^(l)]_(q)— in which q is an integer selected from            1, 2, 3 or 4, and R^(k) and R^(l) are hydrogen;        -   X⁴ is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R^(i))—,            —N(R^(j))—C(O)—, —N(R^(j))—C(O)O—, —C(O)—N(R^(j))—, —S—,            —SO—, —SO₂—, —S(O)₂N(R^(j))—, or —N(R^(j))SO₂— wherein R^(j)            is selected from hydrogen or methyl; and        -   Z¹ is (1-6C)alkyl, aryl, heteroaryl or heterocyclyl;            -   and wherein Z¹ is optionally further substituted by one                or more substituent groups independently selected from                oxo, halo, cyano, hydroxy, NR^(m)R^(n), (1-2C)alkoxy,                (1-2C)alkyl, (3-6C)cycloalkyl, (1-2C)alkanoyl,                (1-2C)alkylsulphonyl, aryl, aryloxy, heterocyclyl,                heterocyclyloxy, heterocyclyl-(1-2C)alkyl, heteroaryl,                heteroaryloxy, heteroaryl-(1-2C)alkyl, C(O)NR^(m)R^(n),                NR^(m)C(O)R^(n), NR^(m)S(O)₂R^(n) and S(O)₂NR^(m)R^(n);                wherein R^(m) and R^(n) are each independently selected                from hydrogen or (1-4C)alkyl; or R^(m) and R^(n) can be                linked such that, together with the nitrogen atom to                which they are attached, they form a 4-6 membered                heterocyclic ring;            -   and wherein any alkyl, aryl, heterocyclyl or heteroaryl                group present in a substituent group on Z¹ is optionally                further substituted by halo, cyano, hydroxy,                NR^(c)R^(p), (1-2C)alkoxy, or (1-2C)alkyl; wherein R^(o)                and R^(p) are selected from hydrogen or (1-2C)alkyl;

-   (31) A_(4a) and A_(4b) are CR₉ and A₄, is CR₁₀, or one or two of    A_(4a), A_(4b) and A_(4c) are N and the others are CR₉ (in the case    of A_(4a) and A_(4b)) or CR₁₀ (in the case of A_(4c));

-   (32) A_(4a) and A_(4b) are CR₉ and A_(4c) is CR₁₀, or one of A_(4a),    A_(4b) and A_(4c) is N and the others are CR₉ (in the case of A_(4a)    and A_(4b)) or CR₁₀ (in the case of A_(4c));

-   (33) A₅ is selected from N or CR₅, where R₅ is selected from    hydrogen, halo, cyano, hydroxy, NR^(q)R^(u), (1-3C)alkyl,    (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6 membered    heterocyclyl; wherein R^(q) and R^(u) are each independently    selected from hydrogen or (1-3C)alkyl; and wherein any (1-3C)alkyl,    (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6 membered    heterocyclyl group present in a R₅ substituent group is optionally    substituted by one or more substitutents selected from halo, cyano,    hydroxy, NR^(v)R^(w), or (1-3C)alkoxy, wherein R^(v) and R^(w) are    each independently selected from hydrogen or (1-3C)alkyl;

-   (34) A₅ is selected from N or CR₅, where R₅ is selected from    hydrogen, halo, cyano, hydroxy, NR^(q)R^(u), (1-3C)alkyl, or    (1-3C)alkoxy; wherein R^(q) and R^(u) are each independently    selected from hydrogen or (1-3C)alkyl; and wherein any (1-3C)alkyl,    (1-3C)alkoxy group present in a R₅ substituent group is optionally    substituted by one or more substitutents selected from halo, cyano,    hydroxy, NR^(v)R^(w), or (1-2C)alkoxy, wherein R^(v) and R^(w) are    each independently selected from hydrogen or (1-2C)alkyl;

-   (35) Ring A is:    -   a fused 5 or 6 membered heteroaryl ring comprising one or two        heteroatoms independently from N, S or O; or    -   a fused 5, 6 or 7-membered heterocyclic ring comprising one or        two heteroatoms independently from N, S or O;

-   (36) A₆ is selected from N, O, S, S(O)₂, CR₆, C(R₆)₂, NR₆₀,    -   where R₆ is selected from hydrogen, oxo, fluoro, chloro,        (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or (1-2C)haloalkyl;        and    -   R₆₀ is hydrogen, O⁻, (1-6C)alkyl, —C(O)—R₆₁, —C(O)O—R₆₁, or        —C(O)N(R₆₂)R₆₁, wherein R₆₁ is selected from hydrogen,        (1-6C)alkyl, aryl, 5 or 6 membered heteroaryl or 5 or 6 membered        heterocyclyl and R₆₂ is selected from hydrogen or (1-2C)alkyl;

-   (37) A₆ is selected from N, O, S, S(O)₂, CR₆, C(R₆)₂, NR₆₀,    -   where R₆ is selected from hydrogen, oxo, (1-2C)alkyl,        (1-2C)alkoxy, (1-2C)haloalkoxy or (1-2C)haloalkyl; and    -   R₆₀ is hydrogen, O⁻, (1-6C)alkyl, —C(O)—R₆₁, —C(O)O—R₆₁, or        —C(O)N(R₆₂)R₆₁, wherein R₆₁ is selected from hydrogen or        (1-6C)alkyl, and R₆₂ is selected from hydrogen or (1-2C)alkyl;

-   (38) A₇ is selected from N, O, CR₇, S, S(O)₂, C(R₇)₂, NR₇₀, where    R₇₀ is hydrogen, O⁻, (1-6C)alkyl, —C(O)—R₇₁, —C(O)O—R₇₁, or    —C(O)N(R₇₂)R₇₁, wherein R₇₁ is selected from hydrogen, (1-6C)alkyl,    aryl, 5 or 6 membered heteroaryl or 5 or 6 membered heterocyclyl and    R₇₂ is selected from hydrogen or (1-2C)alkyl;

-   (39) A₇ is selected from N, O, CR₇, S, S(O)₂, C(R₇)₂, NR₇₀, where    R₇₀ is hydrogen, O⁻, (1-6C)alkyl, —C(O)—R₇₁, —C(O)O—R₇₁, or    —C(O)N(R₇₂)R₇₁, wherein R₇₁ is selected from hydrogen, (1-6C)alkyl,    aryl, 5 or 6 membered heteroaryl or 5 or 6 membered heterocyclyl and    R₇₂ is selected from hydrogen or (1-2C)alkyl;

-   (40) R₇ is selected from halo, cyano, oxo, or a group

W²—X²—Y²—X³—Z²

-   -   wherein        -   W² is absent or a linker group of the formula            —[CR^(x)R^(y)]_(r)— in which r is an integer selected from            1, 2, or 3, and R^(x) and R^(y) are each independently            selected from hydrogen or (1-2C)alkyl;        -   X² is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R^(z))—,            —N(R^(z))—C(O)—, —N(R^(z))—C(O)O—, —C(O)—N(R^(z))—, —S—,            —SO—, —SO₂—, —S(O)₂N(R^(z))—, or —N(R^(z))SO₂, wherein R^(z)            is selected from hydrogen or methyl;        -   Y² is absent or a linker group of the formula            —[CR^(aa)R^(bb)]_(s)— in which s is an integer selected from            1, 2, 3 or 4, and R^(aa) and R^(bb) are each independently            selected from hydrogen or (1-2C)alkyl;        -   X³ is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R^(cc))—,            —N(R^(cc))—C(O)—, —N(R^(cc))—C(O)O—, —C(O)—N(R^(cc))—, —S—,            —SO—, —SO₂—, —S(O)₂N(R^(cc))—, or —N(R^(cc))SO₂, wherein            R^(c)C is selected from hydrogen or methyl; and        -   Z² is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, aryl,            (3-6C)cycloalkyl, heteroaryl, or heterocyclyl,        -   and wherein Z² is optionally further substituted by one or            more substituent groups independently selected from oxo,            halo, cyano, hydroxy, caboxy, NR^(dd)R^(ee), (1-4C)alkoxy,            (1-4C)alkyl, (1-2C)alkanoyl, (1-2C)alkylsulphonyl,            C(O)NR^(dd)R^(ee), NR^(dd)C(O)R^(ee), NR^(dd)SO₂R^(ee) and            SO₂NR^(dd)R^(ee); wherein R^(dd) and R^(ee) are each            independently selected from hydrogen, (1-4C)alkyl,            (3-6C)cycloalkyl; or R^(dd) and R^(ee) can be linked such            that, together with the nitrogen atom to which they are            attached, they form a 4-6 membered heterocyclic ring;        -   and wherein any alkyl, aryl, heterocyclyl or heteroaryl            group present in a substituent group on Z² is optionally            further substituted by halo, cyano, nitro, hydroxy, caboxy,            NR^(ff)R^(gg), (1-2C)alkoxy, or (1-2C)alkyl; wherein R^(ff)            and R^(gg) are selected from hydrogen or (1-2C)alkyl;

-   (41) R₇ is selected from halo, cyano, oxo, or a group

W²—X²—Y²—X³—Z²

-   -   wherein        -   W² is absent or a linker group of the formula            —[CR^(x)R^(y)]_(r)— in which r is an integer selected from            1, 2, or 3, and R^(x) and R^(y) are each independently            selected from hydrogen or (1-2C)alkyl;        -   X² is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R^(z))—,            —N(R^(z))—C(O)—, —N(R^(z))—C(O)O—, —C(O)—N(R^(z))—, —S—,            —SO—, —SO₂—, —S(O)₂N(R^(z))—, or —N(R^(z))SO₂, wherein R^(z)            is selected from hydrogen or methyl;        -   Y² is absent or a linker group of the formula            —[CR^(aa)R^(bb)]_(s)— in which s is an integer selected from            1, 2, 3 or 4, and R^(aa) and R^(bb) are each independently            selected from hydrogen or (1-2C)alkyl;        -   X³ is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R^(cc))—,            —N(R^(c))—C(O)—, —N(R^(cc))—C(O)O—, —C(O)—N(R^(cc))—, —S—,            —SO—, —SO₂—, —S(O)₂N(R^(cc))—, or —N(R^(cc))SO₂, wherein            R^(cc) is selected from hydrogen or methyl; and        -   Z² is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl,            (3-6C)cycloalkyl, 5 or 6 membered heteroaryl, or 5 or 6            membered heterocyclyl,        -   and wherein Z² is optionally further substituted by one or            more substituent groups independently selected from oxo,            halo, cyano, hydroxy, caboxy, NR^(dd)R^(ee), (1-4C)alkoxy,            (1-4C)alkyl, (1-2C)alkanoyl, (1-2C)alkylsulphonyl,            C(O)NR^(dd)R^(ee), NR^(dd)C(O)R^(ee), NR^(dd)SO₂R^(ee) and            SO₂NR^(dd)R^(ee); wherein R^(dd) and R^(ee) are each            independently selected from hydrogen, (1-4C)alkyl,            (3-6C)cycloalkyl; or R^(dd) and R^(ee) can be linked such            that, together with the nitrogen atom to which they are            attached, they form a 4-6 membered heterocyclic ring;

-   (42) m is 0 or 1;

-   (43) m is 0;

-   (44) m is 1;

-   (45) m is 2;

-   (46) R₁₁ is selected from halo, cyano, oxo, or a group

W²—X²—Y²—X³—Z²

-   -   wherein        -   W² is absent or a linker group of the formula            —[CR^(x)R^(y)]_(r)— in which r is an integer selected from            1, 2, or 3, and R^(x) and R^(y) are each independently            selected from hydrogen or (1-2C)alkyl;        -   X² is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R^(z))—,            —N(R^(z))—C(O)—, —N(R^(z))—C(O)O—, —C(O)—N(R^(z))—, —S—,            —SO—, —SO₂—, —S(O)₂N(R^(z))—, or —N(R^(z))SO₂, wherein R^(z)            is selected from hydrogen or methyl;        -   Y² is absent or a linker group of the formula            —[CR^(aa)R^(bb)]_(s)— in which s is an integer selected from            1, 2, 3 or 4, and R^(aa) and R^(bb) are each independently            selected from hydrogen or (1-2C)alkyl;        -   X³ is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R^(cc))—,            —N(R^(cc))—C(O)—, —N(R^(cc))—C(O)O—, —C(O)—N(R^(cc))—, —S—,            —SO—, —SO₂—, —S(O)₂N(R^(cc))—, or —N(R^(cc))SO₂, wherein            R^(cc) is selected from hydrogen or methyl; and        -   Z² is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, aryl,            (3-6C)cycloalkyl, heteroaryl, or heterocyclyl,            -   and wherein Z² is optionally further substituted by one                or more substituent groups independently selected from                oxo, halo, cyano, hydroxy, caboxy, NR^(dd)R^(ee),                (1-4C)alkoxy, (1-4C)alkyl, (1-2C)alkanoyl,                (1-2C)alkylsulphonyl, C(O)NR^(dd)R^(ee),                NR^(dd)C(O)R^(ee), NR^(Id)SO₂R^(ee) and                SO₂NR^(dd)R^(ee); wherein R^(dd) and R^(ee) are each                independently selected from hydrogen, (1-4C)alkyl,                (3-6C)cycloalkyl; or R^(dd) and R^(ee) can be linked                such that, together with the nitrogen atom to which they                are attached, they form a 4-6 membered heterocyclic                ring;            -   and wherein any alkyl, aryl, heterocyclyl or heteroaryl                group present in a substituent group on Z² is optionally                further substituted by halo, cyano, nitro, hydroxy,                caboxy, NR^(ff)R^(gg), (1-2C)alkoxy, or (1-2C)alkyl;                wherein R^(ff) and R^(gg) are selected from hydrogen or                (1-2C)alkyl;

-   (47) R₁₁ is selected from halo, cyano, oxo, or a group

W²—X²—Y²—X³—Z²

-   -   wherein        -   W² is absent or a linker group of the formula            —[CR^(x)R^(y)]_(r)— in which r is an integer selected from            1, 2, or 3, and R^(x) and Ry are each independently selected            from hydrogen or (1-2C)alkyl;        -   X² is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R^(z))—,            —N(R^(z))—C(O)—, —N(R^(z))—C(O)O—, —C(O)—N(R^(z))—, —S—,            —SO—, —SO₂—, —S(O)₂N(R^(z))—, or —N(R^(z))SO₂, wherein R^(z)            is selected from hydrogen or methyl;        -   Y² is absent or a linker group of the formula            —[CR^(aa)R^(bb)]_(s)— in which s is an integer selected from            1, 2, 3 or 4, and R^(aa) and R^(bb) are each independently            selected from hydrogen or (1-2C)alkyl;        -   X³ is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R^(cc))—,            —N(R^(cc))—C(O)—, —N(R^(cc))—C(O)O—, —C(O)—N(R^(cc))—, —S—,            —SO—, —SO₂—, —S(O)₂N(R^(cc))—, or —N(R^(cc))SO₂, wherein            R^(cc) is selected from hydrogen or methyl; and        -   Z² is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl,            (3-6C)cycloalkyl, 5 or 6 membered heteroaryl, or 5 or 6            membered heterocyclyl,            -   and wherein Z² is optionally further substituted by one                or more substituent groups independently selected from                oxo, halo, cyano, hydroxy, caboxy, NR^(dd)R^(ee),                (1-4C)alkoxy, (1-4C)alkyl, (1-2C)alkanoyl,                (1-2C)alkylsulphonyl, C(O)NR^(dd)R^(ee),                NR^(dd)C(O)R^(ee), NR^(dd)SO₂R^(ee) and                SO₂NR^(dd)R^(ee); wherein R^(dd) and R^(ee) are each                independently selected from hydrogen, (1-4C)alkyl,                (3-6C)cycloalkyl; or R^(dd) and R^(ee) can be linked                such that, together with the nitrogen atom to which they                are attached, they form a 4-6 membered heterocyclic                ring;

-   (48) Q is a group of formula III as defined herein;

-   (49) Q is a group of formula Ill as defined herein in which Ring A    is a fused 5 or 6-membered heterocyclic or ring comprising one N    atom;

-   (50) Q is a group of formula:

-   -   wherein R₇, R₁₁ and m each have any one of the definitions set        out herein.

-   (51) Q is a group of formula:

-   -   wherein R₇ has any one of the definitions set out herein.

-   (52) Q is a group of formula:

-   -   wherein R₇ is a group

W²—X²—Y²—X³—Z²

-   -   wherein        -   W² is a linker group of the formula —[CR^(x)R^(y)]_(r)— in            which r is 1, R^(x) is hydrogen and R^(y) is selected from            hydrogen or methyl;        -   X² is absent;        -   Y² is absent;        -   X³ is absent; and        -   Z² is a 4, 5, 6 or 7-membered nitrogen-linked heterocyclyl            optionally comprising one further nitrogen atom,        -   and wherein Z² is optionally further substituted by one or            more substituent groups independently selected from oxo,            halo, cyano, hydroxy, caboxy, NR^(dd)R^(ee), (1-4C)alkoxy,            (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl,            (2C)alkanoyl, (1-2C)alkylsulphonyl, C(O)NR^(dd)R^(ee),            NR^(dd)C(O)R^(ee), NR^(dd)SO₂R^(ee) and SO₂NR^(dd)R^(ee);            wherein R^(dd) and R^(ee) are each independently selected            from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl;

-   (53) Q is a group of formula:

-   -   wherein R₇ is a group

W²—X²—Y²—X³—Z²

-   -   wherein        -   W² is a linker group of the formula —[CR^(x)R^(y)]_(r)— in            which r is 1, R^(x) is hydrogen and R^(y) is selected from            hydrogen or methyl;        -   X² is absent;        -   Y² is absent;        -   X³ is absent; and        -   Z² is a 4, 5, 6 or 7-membered nitrogen-linked heterocyclyl            optionally comprising one further nitrogen atom,        -   and wherein Z² is optionally further substituted on the            further nitrogen atom by methyl, ethyl, propyl or            cyclopropylmethyl and/or on a carbon atom by methyl, fluoro            or chloro.

Suitably, both A₁ and A₂ are CR₁ and CR₂ respectively, or A₁ is N and A₂is CR₂.

Suitably, R₁ and R₂ are selected from hydrogen or halo (e.g. fluoro).More suitably, R₁ and R₂ are selected from hydrogen or fluoro. Mostsuitably, R₁ and R₂ are hydrogen.

In an embodiment, A₁ and A₂ are CR₁ and CR₂ respectively. Such compoundshave the structural formula IA shown below:

whereinR₁, R₂, R₄ and Q each have any one the definitions set out herein.

Suitably, in the compounds of formula I or IA, R, and R₂ are bothselected from hydrogen or one of R₁ and R₂ is halo (especially fluoro)and the other is hydrogen. Most suitably, both of R₁ and R₂ arehydrogen.

In an embodiment, A₁ and A₂ are both CH. Such compounds have thestructural formula IB shown below:

whereinR₄ and Q each have any one the definitions set out herein.

Suitably, in compounds of formula I, IA or IB, R₄ has any one of thedefinitions set out in paragraphs (11) to (22) above. Most suitably, R₄is as defined in any one of paragraphs (14), (15), (16) or (17) above.In a particular embodiment, R₄ is methyl, fluoro or chloro.

Suitably, in compounds of formula I, IA or IB, Q is as defined in anyone of paragraphs (23) to (53) above. In a particular embodiment, Q isas defined in any one of paragraphs (50), (51), (52) or (53) above.

In an embodiment of the compounds of formula I, IA or IB, Q has one ofthe structural formulae IIa, IIb, IIc, IId, IIe, IIIa and IIIb shownbelow:

wherein R₉, R₁₀, A₅, A₆, A₇, R₁₁ and m each have any one of thedefinitions hereinbefore;ring A1 is a fused 5-membered carbocyclic ring, 5-membered heterocyclicring or 5-membered heteroaryl ring;ring A2 is a fused 6 or 7-membered carbocyclic ring, 6 or 7-memberedheterocyclic ring or 6-membered heteroaryl ring.

Suitably, in compounds of formula I, IA or IB, ring A1 is a fused5-membered heterocyclic ring or 5-membered heteroaryl ring comprisingone or two heteroatoms selected from N, O or S.

Suitably, in compounds of formula I, IA or IB ring A2 is a fused6-membered heterocyclic or 6-membered heteroaryl comprising one or twoheteroatoms selected from N, O or S.

In an embodiment of the compounds of formula I, IA or IB, Q is a groupof structural formula IIIa or IIIb as shown above.

In a particular embodiment of the compounds of formula I, IA or IB, Q isa group of structural formula IIIb as defined above.

In an embodiment of the compounds of formula I, IA or IB Q is selectedfrom one of the following:

wherein A₅, R₅, R₆, R₇, R₆₀, R₁₁ and m each have any one of thedefinitions herein.

In an embodiment of the compounds of formula I, IA or IB, Q is selectedfrom:

wherein A₅, R₆₀, R₇, R₁₁ and m each have any one of the definitionsherein.

In an embodiment of the compounds of formula I, IA or IB, Q is selectedfrom:

wherein R₅, R₆₀, R₇, R₁₁ and m each have any one of the definitionsherein.

In a particular embodiment of the compounds of formula I, IA or IB, Q isselected from:

wherein R₇ has any one of the definitions set out hereinbefore.

In a particular embodiment of the compounds of formula I, IA or IB, Qis:

wherein R₅, R₇, R₁₁ and m each have any one of the definitions herein.

In a particular embodiment of the compounds of formula I or IA, Q is:

wherein R₇ has any one of the definitions set out hereinbefore.

Suitably, R₇ is as defined in any one of paragraphs (50), (51), (52) or(53) above.

Particular compounds of the present invention include any one of thecompounds exemplified in the present application, or a pharmaceuticallyacceptable salt or solvate thereof, and, in particular, any one of thefollowing:

-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)isoquinoline-7-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-methoxyethoxy)quinoline-6-carboxamide;-   N-(4-methyl-3-(2-oxo-2H-chromene-6-carboxamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(3-(3,4-dimethoxybenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(3-(2,3-dihydrobenzofuran-5-carboxamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1-methylindoline-5-carboxamide;-   N-(4-methyl-3-(1-oxo-1,3-dihydroisobenzofuran-5-carboxamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(3-(chroman-6-carboxamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinazoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-4-methoxyquinoline-6-carboxamide;-   2-chloro-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(thiazol-4-ylmethoxy)nicotinamide;-   N-(4-methyl-3-(2-methyl-2,3-dihydrobenzofuran-5-carboxamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(3-(1,3-dihydroisobenzofuran-5-carboxamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1-methyl-1H-indole-5-carboxamide;-   N-(3-(benzofuran-5-carboxamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(3-(benzo[b]thiophene-5-carboxamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(4-methyl-3-(4-(pyridin-2-ylmethoxy)benzamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(4-methyl-3-(4-(thiazol-5-ylmethoxy)benzamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   tert-butyl    (2-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinolin-2-yl)oxy)ethyl)carbamate;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-4-methoxy-2-(2-methoxyethoxy)quinoline-6-carboxamide;-   6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinoline    1-oxide;-   4-cyano-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(pyridin-2-ylmethoxy)nicotinamide;-   N-(3-(4-methoxy-3-methylbenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(3-(4-methoxybenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(3-(3-chloro-4-methoxybenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methoxyquinoline-6-carboxamide;-   tert-butyl    5-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)indoline-1-carboxylate;-   tert-butyl    6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-morpholinoquinoline-6-carboxamide;-   N5-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-N2-methylpyridine-2,5-dicarboxamide;-   N-(4-methyl-3-(5,6,7,8-tetrahydronaphthalene-2-carboxamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   tert-butyl    (3-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinolin-2-yl)oxy)propyl)carbamate;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoxaline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-phenylnicotinamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-((3-iodophenyl)amino)nicotinamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methylquinoline-6-carboxamide;-   N-(3-(3-methoxybenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(3-(4-bromo-3-methoxybenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(3-(4-methoxy-3,5-dimethylbenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1,6-naphthyridine-3-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1,7-naphthyridine-3-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1,8-naphthyridine-3-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)isoquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-3-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-carboxamide;-   (R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((1-methylpyrrolidin-3-yl)oxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((1-methylpiperidin-4-yl)oxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(3-(dimethylamino)propoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(3-(piperidin-1-yl)propoxy)quinoline-6-carboxamide;-   (S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((1-methylpyrrolidin-2-yl)methoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(piperidin-1-yl)ethoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(3-morpholinopropoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(3-(pyrrolidin-1-yl)propoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(3-fluoropiperidin-1-yl)ethoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((2-(dimethylamino)ethyl)(methyl)amino)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(pyrrolidin-1-yl)ethyl)quinoline-6-carboxamide;-   2-(2-(azetidin-1-yl)ethoxy)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(2-methylpyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(dimethylamino)ethoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)quinoline-6-carboxamide;-   (S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(3-fluoropyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-morpholinoethoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(pyrrolidin-1-ylmethyl)quinoline-6-carboxamide    formate;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(pyrrolidin-1-yi)propoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(dimethylamino)ethyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((4-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((dimethylamino)methyl)quinoline-6-carboxamide;-   2-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((1-(pyrrolidin-1-yl)propan-2-yl)oxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(4-methylpiperazin-1-yl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-hydroxyethyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(3-(methylamino)propoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-ethylquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((N-methylpropionamido)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(methylamino)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-propionamidoethoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((2-propionamidoethyl)amino)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)indoline-5-carboxamide;-   tert-butyl    ((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)-1,2,3,4-tetrahydroquinolin-2-yl)methyl)(methyl)carbamate;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((methylamino)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((dimethylamino)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide;-   2-(2-aminoethoxy)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-6-carboxamide;-   2-amino-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)benzo[d]thiazole-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxamide;-   N-(3-(4-hydroxybenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(phenylamino)nicotinamide;-   2-amino-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-4-methoxybenzo[d]thiazole-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(1H-1,2,4-triazol-1-yl)isonicotinamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1H-indazole-5-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-morpholinoisonicotinamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide;-   N-(4-methyl-3-(4-(thiazol-4-ylmethoxy)benzamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(ethylamino)nicotinamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   6-amino-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)nicotinamide;-   2-amino-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)isonicotinamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(1H-pyrazol-1-yl)nicotinamide;-   N-(3-(4-(1H-pyrazol-1-yl)benzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(4-methyl-3-(6-methyl-2-naphthamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-3-methyl-4-oxo-3,4-dihydroquinazoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-4-(2-(dimethylamino)ethylamino)-2-methylquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-4-(3-(dimethylamino)propylamino)-2-methylquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-4-(methyl(1-methylpyrrolidin-3-yl)amino)quinoline-6-carboxamide;-   N-(3-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-methylquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)benzo[d]thiazole-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(methylamino)benzo[d]thiazole-6-carboxamide;-   2-amino-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)benzo[d]thiazole-7-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-4-(2-(pyrrolidin-1-yl)ethylamino)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-4-(2-morpholinoethylamino)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methylquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-(1-methylpiperidin-4-yloxy)phenylamino)nicotinamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-(4-methylpiperazin-1-yl)propylamino)nicotinamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-((4-methylpiperazin-1-yl)methyl)phenylamino)nicotinamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-((dimethylamino)methyl)phenylamino)nicotinamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-(3-(dimethylamino)pyrrolidin-1-yl)phenylamino)nicotinamide;-   N-(3-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-methylquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(trifluoromethyl)phenyl)-2-methylquinoline-6-carboxamide;-   N-(5-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methylquinoline-6-carboxamide;-   N-(5-(benzo[d][1,3]dioxole-5-carboxamido)-2-methylphenyl)quinoline-6-carboxamide;-   N-(5-(3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-carboxamido)-2-methylphenyl)-2-methylquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-ethylphenyl)quinoline-6-carboxamide;-   N-(4-methyl-3-(2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamido)phenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxamide;-   N-(4-methyl-3-(2-methylquinoline-6-carboxamido)phenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-8-fluoroquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(methoxymethyl)quinoline-6-carboxamide;-   N-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide;-   N-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide;-   N-(2-cyano-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(1-hydroxyethyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-morpholinoethyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(isopropoxymethyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(((tetrahydrofuran-2-yl)methoxy)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((2-(pyrrolidin-1-yl)ethoxy)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-5-((2-(pyrrolidin-1-yl)ethyl)amino)quinoline-3-carboxamide;-   N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-3-((2-methoxyethyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(isobutoxymethyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(1-methoxyethyl)quinoline-6-carboxamide;-   (S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-3-(2-(pyrrolidin-1-yl)ethoxy)isoquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-5-(2-hydroxyethyl)quinoline-3-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-5-(2-(pyrrolidin-1-yl)ethyl)quinoline-3-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1,2-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-8-(2-methoxyethoxy)quinoline-6-carboxamide;-   5-allyl-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-3-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-8-((2-(dimethylamino)ethyl)(methyl)amino)quinoline-6-carboxamide;-   3-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinolin-2-yl)(methyl)amino)propanoic    acid;-   tert-butyl    (4-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinolin-2-yl)oxy)butyl)carbamate;-   N-(5-amino-2-((dimethylamino)methyl)phenyl)-2-methylquinoline-6-carboxamide;-   N-(5-amino-2-((dimethylamino)methyl)phenyl)-2-methylquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(methoxymethyl)phenyl)-2-methylquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(hydroxymethyl)phenyl)-2-methylquinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1-methyl-1,3-dihydrobenzo[c]isothiazole-5-carboxamide    2,2-dioxide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(pyrrolidin-1-ylmethyl)quinoline-6-carboxamide;-   2-(azetidin-1-ylmethyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(piperidin-1-ylmethyl)quinoline-6-carboxamide-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(piperazin-1-ylmethyl)quinoline-6-carboxamide;-   (S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((2-methylpyrrolidin-1-yl)methyl)quinoline-6-carboxamide;-   (R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((2-methylpyrrolidin-1-yl)methyl)quinoline-6-carboxamide;-   2-((4-(tert-butyl)piperazin-1-yl)methyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)quinoline-6-carboxamide;-   2-((4-cyclopropylpiperazin-1-yl)methyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)quinoline-6-carboxamide;-   2-((4-(sec-butyl)piperazin-1-yl)methyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)quinoline-6-carboxamide;-   2-(2-azaspiro[3.3]heptan-2-ylmethyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((3-methylazetidin-1-yl)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((3,3-dimethylazetidin-1-yl)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethyl-1,4-diazepan-1-yl)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-isopropylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(3-(piperidin-1-yl)propoxy)quinoline-6-carboxamide-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(3-(pyrrolidin-1-yl)propoxy)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide;-   N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-(3-(piperidin-1-yl)propoxy)quinoline-6-carboxamide;-   (rac)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((2-methylpyrrolidin-1-yl)methyl)quinoline-6-carboxamide;-   2-((4-(tert-butyl)piperazin-1-yl)methyl)-N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide;-   N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-(piperazin-1-ylmethyl)quinoline-6-carboxamide;-   2-((4-(sec-butyl)piperazin-1-yl)methyl)-N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide;-   N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((4-cyclopropylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((4-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((4-isopropylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-(pyrrolidin-1-ylmethyl)quinoline-6-carboxamide-   2-(azetidin-1-ylmethyl)-N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide;-   N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((3-methylazetidin-1-yl)methyl)quinoline-6-carboxamide;-   N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((3,3-dimethylazetidin-1-yl)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((4-isopropylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   2-(azetidin-1-ylmethyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((2-methylpyrrolidin-1-yl)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((2-methylpyrrolidin-1-yl)methyl)quinoline-6-carboxamide;-   (R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((3-fluoropyrrolidin-1-yl)methyl)quinoline-6-carboxamide;-   (S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((3-fluoropyrrolidin-1-yl)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((3-methoxypyrrolidin-1-yl)methyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(piperidin-1-ylmethyl)quinoline-6-carboxamide;-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-vinylphenyl)-2-methylquinoline-6-carboxamide;-   N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide;-   (R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethyl-2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   (S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethyl-2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide-   N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(1-(4-ethylpiperazin-1-yl)ethyl)quinoline-6-carboxamide;-   N-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   2-(azetidin-1-ylmethyl)-N-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide;-   (S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-isopropyl-2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide-   (R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-isopropyl-2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide;-   or a pharmaceutically acceptable salt or solvate thereof.

The various functional groups and substituents making up the compoundsof the present invention are typically chosen such that the molecularweight of the compound does not exceed 1000. More usually, the molecularweight of the compound will be less than 750, for example less than 700,or less than 650, or less than 600, or less than 550. More preferably,the molecular weight is less than 525 and, for example, is 500 or less.

Suitable or preferred features of any compounds of the present inventionmay also be suitable features of any other aspect.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic,formic, citric or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001),for example by synthesis from optically active starting materials or byresolution of a racemic form. Some of the compounds of the invention mayhave geometric isomeric centres (E- and Z-isomers). It is to beunderstood that the present invention encompasses all optical,diastereoisomers and geometric isomers and mixtures thereof that possessHSF1 inhibitory activity.

The present invention also encompasses compounds of the invention asdefined herein which comprise one or more isotopic substitutions. Forexample, H may be in any isotopic form, including ¹H, ²H (D) and ³H (T);C may be in any isotopic form including ¹²C, ¹³C, and ¹⁴C; and O may bein any isotopic form, including ¹⁶O and ¹⁸O; and the like.

It is also to be understood that certain compounds of the invention mayexist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms that possess HSF1 inhibitory activity.

It is also to be understood that certain compounds of the invention mayexhibit polymorphism, and that the invention encompasses all such formsthat possess HSF1 inhibitory activity.

Compounds of the invention may exist in a number of different tautomericforms and references to compounds of the invention include all suchforms. For the avoidance of doubt, where a compound can exist in one ofseveral tautomeric forms, and only one is specifically described orshown, all others are nevertheless embraced by compounds of theinvention. Examples of tautomeric forms include keto-, enol-, andenolate-forms, as in, for example, the following tautomeric pairs:keto/enol (illustrated below), imine/enamine, amide/imino alcohol,amidine/amidine, nitroso/oxime, thioketone/enethiol, andnitro/aci-nitro.

Compounds of the invention containing an amine function may also formN-oxides. A reference herein to a compound of the formula I thatcontains an amine function also includes the N-oxide. Where a compoundcontains several amine functions, one or more than one nitrogen atom maybe oxidised to form an N-oxide. Particular examples of N-oxides are theN-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containingheterocycle. N-Oxides can be formed by treatment of the correspondingamine with an oxidizing agent such as hydrogen peroxide or a per-acid(e.g. a peroxycarboxylic acid), see for example Advanced OrganicChemistry, by Jerry March, 4^(th) Edition, Wiley Interscience, pages.More particularly, N-oxides can be made by the procedure of L. W. Deady(Syn. Comm. 1977, 7, 509-514) in which the amine compound is reactedwith m-chloroperoxybenzoic acid (MCPBA), for example, in an inertsolvent such as dichloromethane.

The compounds of the invention may be administered in the form of apro-drug which is broken down in the human or animal body to release acompound of the invention. A pro-drug may be used to alter the physicalproperties and/or the pharmacokinetic properties of a compound of theinvention. A pro-drug can be formed when the compound of the inventioncontains a suitable group or substituent to which a property-modifyinggroup can be attached. Examples of pro-drugs include in vivo cleavableester derivatives that may be formed at a carboxy group or a hydroxygroup in a compound of the invention and in-vivo cleavable amidederivatives that may be formed at a carboxy group or an amino group in acompound of the invention.

Accordingly, the present invention includes those compounds of theformula I or IA as defined hereinbefore when made available by organicsynthesis and when made available within the human or animal body by wayof cleavage of a pro-drug thereof. Accordingly, the present inventionincludes those compounds of the formula I that are produced by organicsynthetic means and also such compounds that are produced in the humanor animal body by way of metabolism of a precursor compound, that is acompound of the formula I may be a synthetically-produced compound or ametabolically-produced compound.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I or IA is one that is based on reasonable medical judgement asbeing suitable for administration to the human or animal body withoutundesirable pharmacological activities and without undue toxicity.

Various forms of pro-drug have been described, for example in thefollowing documents:—

-   a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder,    et al. (Academic Press, 1985);-   b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991);-   d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988);-   f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);-   g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”,    A.C.S. Symposium Series, Volume 14; and-   h) E. Roche (editor), “Bioreversible Carriers in Drug Design”,    Pergamon Press, 1987.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses a carboxy group is, for example, an in vivocleavable ester thereof. An in vivo cleavable ester of a compound of theformula I containing a carboxy group is, for example, a pharmaceuticallyacceptable ester which is cleaved in the human or animal body to producethe parent acid. Suitable pharmaceutically acceptable esters for carboxyinclude C₁₋₆alkyl esters such as methyl, ethyl and tert-butyl,C₁₋₆alkoxymethyl esters such as methoxymethyl esters,C₁₋₆alkanoyloxymethyl esters such as pivaloyloxymethyl esters,3-phthalidyl esters, C₃-cycloalkylcarbonyloxy-C₁₋₆alkyl esters such ascyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,2-oxo-1,3-dioxolenylmethyl esters such as5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters andC₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl esters such as methoxycarbonyloxymethyland 1-methoxycarbonyloxyethyl esters.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses a hydroxy group is, for example, an in vivocleavable ester or ether thereof. An in vivo cleavable ester or ether ofa compound of the formula I containing a hydroxy group is, for example,a pharmaceutically acceptable ester or ether which is cleaved in thehuman or animal body to produce the parent hydroxy compound. Suitablepharmaceutically acceptable ester forming groups for a hydroxy groupinclude inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters). Further suitable pharmaceuticallyacceptable ester forming groups for a hydroxy group includeC₁₋₁₀alkanoyl groups such as acetyl, benzoyl, phenylacetyl andsubstituted benzoyl and phenylacetyl groups, C₁₋₁₀alkoxycarbonyl groupssuch as ethoxycarbonyl, N,N—(C₁₋₆)₂carbamoyl, 2-dialkylaminoacetyl and2-carboxyacetyl groups. Examples of ring substituents on thephenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl,N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and4-(C₁₋₄alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptableether forming groups for a hydroxy group include α-acyloxyalkyl groupssuch as acetoxymethyl and pivaloyloxymethyl groups.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses a carboxy group is, for example, an in vivocleavable amide thereof, for example an amide formed with an amine suchas ammonia, a C₁₋₄alkylamine such as methylamine, a (C₁₋₄alkyl)₂ aminesuch as dimethylamine, N-ethyl-N-methylamine or diethylamine, aC₁₋₄alkoxy-C₂₋₄alkylamine such as 2-methoxyethylamine, aphenyl-C₁₋₄alkylamine such as benzylamine and amino acids such asglycine or an ester thereof.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses an amino group is, for example, an in vivocleavable amide derivative thereof. Suitable pharmaceutically acceptableamides from an amino group include, for example an amide formed withC₁₋₁₀alkanoyl groups such as an acetyl, benzoyl, phenylacetyl andsubstituted benzoyl and phenylacetyl groups. Examples of ringsubstituents on the phenylacetyl and benzoyl groups include aminomethyl,N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl,piperazin-1-ylmethyl and 4-(C₁₋₄alkyl)piperazin-1-ylmethyl.

The in vivo effects of a compound of the formula I may be exerted inpart by one or more metabolites that are formed within the human oranimal body after administration of a compound of the formula I. Asstated hereinbefore, the in vivo effects of a compound of the formula Imay also be exerted by way of metabolism of a precursor compound (apro-drug).

It shall also be appreciated that compounds of formula I may also becovalently linked (at any suitable position) to other groups such as,for example, solubilising moieties (for example, PEG polymers), moietiesthat enable them to be bound to a solid support (such as, for example,biotin-containing moieties), and targeting ligands (such as antibodiesor antibody fragments).

Synthesis

In the description of the synthetic methods described herein, it is tobe understood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, can be selected by a person skilled inthe art.

It is understood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reaction conditions utilised.

Necessary starting materials may be obtained by standard procedures oforganic chemistry. The preparation of such starting materials isdescribed in conjunction with the following representative processvariants and within the accompanying Examples. Alternatively necessarystarting materials are obtainable by analogous procedures to thoseillustrated which are within the ordinary skill of an organic chemist.

It will be appreciated that during the synthesis of the compounds of theinvention in the processes defined below, or during the synthesis ofcertain starting materials, it may be desirable to protect certainsubstituent groups to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how suchprotecting groups may be put in place, and later removed.

For examples of protecting groups see one of the many general texts onthe subject, for example, ‘Protective Groups in Organic Synthesis’ byTheodora Green (publisher: John Wiley & Sons). Protecting groups may beremoved by any convenient method described in the literature or known tothe skilled chemist as appropriate for the removal of the protectinggroup in question, such methods being chosen so as to effect removal ofthe protecting group with the minimum disturbance of groups elsewhere inthe molecule.

Thus, if reactants include, for example, groups such as amino, carboxyor hydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

By way of example, a suitable protecting group for an amino oralkylamino group is, for example, an acyl group, for example an alkanoylgroup such as acetyl, an alkoxycarbonyl group, for example amethoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, anarylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroylgroup, for example benzoyl. The deprotection conditions for the aboveprotecting groups necessarily vary with the choice of protecting group.Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonylgroup or an aroyl group may be removed by, for example, hydrolysis witha suitable base such as an alkali metal hydroxide, for example lithiumor sodium hydroxide. Alternatively an acyl group such as atert-butoxycarbonyl group may be removed, for example, by treatment witha suitable acid as hydrochloric, sulfuric or phosphoric acid ortrifluoroacetic acid and an arylmethoxycarbonyl group such as abenzyloxycarbonyl group may be removed, for example, by hydrogenationover a catalyst such as palladium-on-carbon, or by treatment with aLewis acid for example BF₃.OEt₂. A suitable alternative protecting groupfor a primary amino group is, for example, a phthaloyl group which maybe removed by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium, sodium hydroxide or ammonia. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

Resins may also be used as a protecting group.

The compounds of the invention may be prepared using synthetictechniques that are known in the art (as illustrated in the accompanyingexamples).

In a particular aspect, the present invention provides a method ofsynthesising a compound of the formula I as defined herein, or apharmaceutically acceptable salt or solvate thereof, the methodcomprising:

-   -   a) reacting a compound of formula A:

wherein A₁, A₂, and R₄ each have any one of the meanings as definedhereinbefore;with a compound of formula B:

Q-COOH   Formula B

wherein Q is as defined herein; and

-   -   b) optionally thereafter, and if necessary:        -   i) removing any protecting groups present;        -   ii) converting the compound formula I into another compound            of formula I; and/or        -   iii) forming a pharmaceutically acceptable salt or solvate            thereof.

Suitably the coupling reaction between formula A and formula B takesplace in the presence of a suitable solvent. Any suitable solvent orsolvent mixture may be used for this reaction. A person skilled in theart will know how to select suitable solvents or solvent mixtures foruse in these reactions. Examples of suitable solvents include DMA,1,4-dioxane, DMF and toluene.

A person skilled in the art will be able to select appropriate reactionconditions to use in order to facilitate this reaction. Suitably, thereaction is carried out in anhydrous conditions and in the presence ofan inert atmosphere, such as argon or nitrogen. The reaction may also becarried out at room temperature or at an elevated temperature for asuitable time period of, for example, 2 hours to 7 days, or moresuitably 2 to 10 hours. If desired, the reaction mixture may be heatedeither conventionally or by using microwave irradiation.

Suitably the coupling reaction between formula A and formula B takesplace in the presence of a coupling agent. Suitable coupling agents areknown in the art and described in, for example, Chem. Soc. Rev., 2009,38, 606-631. An example of a suitable coupling agent is HATU.

The compound of formula A can be prepared by processes known in the art,and suitably by the processes described herein with reference to theexamples.

The compound of formula B can be prepared by processes known in the art,and suitably by the processes described herein with reference to theexamples.

In step (b) of the above processes, if a suitable protecting group ispresent then additional deprotection conditions may be employed.Suitable protecting groups include tert-butoxycarbonate anddimethylacetal. Typical conditions comprise a suitable acid in asuitable solvent such as trifluoroacetic acid in either DCM or THF.

A racemic compound of formula 1 may be separated using suitable chiralseparation chromatography to furnish the desired enantiomers.

In another aspect, the present invention provides a method ofsynthesising a compound of the formula II, or a pharmaceuticallyacceptable salt or solvate thereof, the method comprising:

-   -   a) reacting a compound of formula C:

wherein Q and R₄ each have any one of the meanings as definedhereinbefore;with a compound of formula D:

wherein A₁ and A₂ are as defined hereinbefore; and

-   -   b) optionally thereafter, and if necessary:        -   i) removing any protecting groups present;        -   ii) converting the compound formula II into another compound            of formula II; and/or        -   iii) forming a pharmaceutically acceptable salt or solvate            thereof.

Suitably the reaction conditions for the coupling between compound C andcompound D are as defined above for the coupling between compounds A andB.

In a further aspect of the invention, there is provided a compound offormula II obtainable by/obtained by/or directly obtained by any one ofthe processes defined or exemplified herein.

Biological Activity

The following biological assays may be used to measure thepharmacological effects of the compounds of the present invention.

Arrayscan Assay

U2OS cells (1500 per well) were plated in 40 μL of DMEM media(containing 10% fetal calf serum and 2 mM Glutamax T-1) in costar384-well plates and left overnight at 37° C. and 5% CO₂ to adhere.

Cells were then dosed with compound diluted in DMSO (120 nL added toeach well to give 0.0313-30 μM concentrations of compound) and incubatedat 37° C. and 5% CO₂. After 1 h of treatment with compound, all wellsexcept min wells were dosed with 17-AAG diluted in DMSO (10 nL added toeach well to give 250 nM final concentration) and plates were incubatedovernight at 37° C. and 5% CO₂. The following day the cells were fixedby addition of 20 μL/well of 12% formaldehyde with 1:1700 Hoechst in PBSfor 10 min at room temperature. The fixative was decanted and the wellswashed once with 50 μL of phosphate buffer saline (PBS). The PBS wassubsequently aspirated, and the cells were permeabilized by addition of20 μL/well of PBS 0.3% Triton X-100 for 20 min at room temperature. Thewells were then washed with 80 μL of PBS prior to the addition of 20 μLof combined primary and secondary antibodies diluted in PBS (1:10 000mouse anti-Hsp72 #SPA-810 purchased from Stressgen and 1:3000 AlexaFluor 488 goat anti-mouse IgG (H+L) #A-11001 molecular probes), for 2 hat room temperature. The wells were then washed with 50 μL of PBS.Finally, 50 μL of PBS was added to each well, and the plates were sealedready to analyze. Analysis was carried out using a Cellomics ArrayscanVTI instrument and the Cellomics Arrayscan Compartmental Analysisalgorithm to measure cellular levels of HSP72. Results are reported asIC₅₀ values for inhibition of HSP72 levels and are averages of at least2 independent measurements.

Cell-Based ELISA (Cellisa) Assay

U2OS cells (5-8×10⁴ cells/mL) or SK-OV-3 cells (5-8×10⁴ cells/mL) wereseeded into 96-well plates and incubated at 37° C. for 48 h. Compoundswere then added at a range of concentrations and incubated for 1 hbefore addition of 17-AAG (250 nM). Cells were then incubated for 18 h.The medium was removed washed 2× with PBS and cells were then fixed withfixing solution (4% paraformaldehyde, 0.3% TritonX-100 in PBS) for 30min at 4° C. The plates were then washed 2× with PBS before blockingwith 5% milk for 30 min at 37° C. After washing the plates 4× with 0.1%Tween-20/deionised water, HSP72 antibody (SPA-810, Enzo Life) was addedfor 1.5 h at 37° C. Following 4× washes, the plates were incubated witheuropium-labelled anti-mouse antibody (0.6 ug/ml) in Delfia assay buffer(Perkin Elmer) for 1 h at 37° C. After washing the plates, Delfiaenhancement solution was added, shaken for 10 min before reading in theEnvision plate reader (Perkin-Elmer) with excitation at 340 nm andemission at 615 nm. The plates were washed again before proteindetermination using the bicinchoninic acid assay (BCA assay, PierceBiotechnology). The europium counts were normalised for the amount ofprotein in each well. The 50% inhibitory concentration value of thecompound was then calculated.

Titre Blue Assay

The cell titre blue viability (Promega, USA) assay provides ahomogenous, fluorometric method for estimating the number of viablecells. It uses the dark blue indicator dye resazurin to measure themetabolic capacity of cells which is an indicator of cell viability.Viable cells are able to reduce resazurin into resorufin (pink) which ishighly fluorescent. Briefly, U2OS or SK-OV-3 (6×10³ cells/mL) wereseeded into 384-well plates and were incubated for 24 h. Compounds (at arange of concentrations) were added using the ECHO 550 liquid handler(Labcyte, USA) and then left at 37° C. for 96 h. Titre blue reagent wasadded to each well and left at 37° C. for 3-4 h. Fluorescence wasmeasured using the Envision machine (Perkin Elmer, UK).

In general, activity possessed by compounds of the formula I, may bedemonstrated in the Arrayscan and Cellisa assays by an IC₅₀ value ofless than 15 μM. Suitably compounds have an IC₅₀ value of less than 10μM in these assays, more suitably less than 5 μM, even more suitablyless than 2 μM and most suitably less than 1 μM. Preferred compounds ofthe invention have an IC₅₀ value of less than 500 nM in the Arrayscanand Cellulisa assays.

The activities of compounds of the invention in the above assay areshown in the accompanying example section.

Pharmaceutical Compositions

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt orsolvate thereof, in association with a pharmaceutically acceptablediluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular,intraperitoneal or intramuscular dosing or as a suppository for rectaldosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

An effective amount of a compound of the present invention for use intherapy of proliferative disease is an amount sufficient tosymptomatically relieve in a warm-blooded animal, particularly a humanthe symptoms of infection, to slow the progression of infection, or toreduce in patients with symptoms of infection the risk of getting worse.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the invention for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.1 mg/kg to 75 mg/kg body weight is received, givenif required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous or intraperitoneal administration, a dose in the range, forexample, 0.1 mg/kg to 30 mg/kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.05 mg/kg to 25 mg/kg body weight will be used. Oraladministration may also be suitable, particularly in tablet form.Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of acompound of this invention.

Therapeutic Uses and Applications

The compounds of the present invention function as inhibitors of HSF1activity. Accordingly, the compounds of the invention are potentiallyuseful agents for the treatment of diseases or conditions in which HSF1activity is implicated.

In one aspect, the present invention provides a compound of formula I,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein for use in therapy.

In another aspect, the present invention provides a method of inhibitingHSF1 activity in a cell, the method comprising administering to saidcell compound of formula I as defined herein, or a pharmaceuticallyacceptable salt or solvate thereof.

In a further aspect, the present invention provides a method ofinhibiting HSF1 in vitro or in vivo, said method comprising contacting acell with an effective amount of a compound, or a pharmaceuticallyacceptable salt or solvate thereof, as defined herein.

In another aspect, the present invention provides a method of inhibitingHSF1 activity in a human or animal subject in need of such inhibition,the method comprising administering to said subject an effective amountof a compound of formula I as defined herein, or a pharmaceuticallyacceptable salt or solvate thereof.

In another aspect, the present invention provides a compound of formulaI as defined herein, or a pharmaceutically acceptable salt or solvatethereof for use in the treatment of disease or condition associated withHSF1 activity.

In another aspect, the present invention provides the use of a compoundof formula I as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, in the manufacture of a medicament for use in thetreatment of disease or condition associated with HSF1 activity.

In yet another aspect, the present invention provides a method oftreating a proliferative disorder in a human or animal subject, themethod comprising administering to said subject a therapeuticallyacceptable amount of a compound of formula I as defined herein, or apharmaceutically acceptable salt or solvate thereof.

HSF1 activity has been implicated in several diseases, including cancer,and autoimmune, and viral diseases.

The broad activity of HSF1 and the role it plays in many disease statesis discussed in the scientific literature, see for example:

-   Evans, C. G.; Chang, L.; Gestwicki, J. E., Heat Shock Protein 70    (Hsp70) as an Emerging Drug Target. J Med Chem 2010, 53 (12),    4585-4602;-   Calderwood, S. K.; Khaleque, M. A.; Sawyer, D. B.; Ciocca, D. R.,    Heat shock proteins in cancer: chaperones of tumorigenesis. Trends    Biochem Sci 2006, 31 (3), 164-172;-   Dai, C.; Whitesell, L.; Rogers, A. B.; Lindquist, S., Heat shock    factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell    2007, 130 (6), 1005-1018;-   Whitesell, L.; Lindquist, S., Inhibiting the transcription factor    HSF1 as an anticancer strategy. Expert Opin Ther Tar 2009, 13 (4),    469-478; and-   Powers, M. V.; Workman, P., Inhibitors of the heat shock response:    Biology and pharmacology. Febs Lett 2007, 581 (19), 3758-3769;    the entire contents of which are incorporated herein by reference.

HSF1 and other heat shock proteins (whose expression is increased byHSF1) are over-expressed in, or have otherwise been implicated in,breast, endometrial, fibrosarcoma, gastric, kidney, liver, lung,lymphoma, neuroectodermal, neuroblastoma, Ewing's sarcoma, prostate,skin, squamous cell, and testicular cancers, leukemia (e.g.promyelocytic leukemia), head and neck cancer, and Hodgkin's disease.

In yet another aspect, the present invention provides a compound offormula I as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, for use in the treatment of a proliferative disorder.

In yet another aspect, the present invention provides the use of acompound of formula I as defined herein, or a pharmaceuticallyacceptable salt or solvate thereof, in the manufacture of a medicamentfor use in the treatment of a proliferative disorder.

The term “proliferative disorder” are used interchangeably herein andpertain to an unwanted or uncontrolled cellular proliferation ofexcessive or abnormal cells which is undesired, such as, neoplastic orhyperplastic growth, whether in vitro or in vivo. Examples ofproliferative conditions include, but are not limited to, pre-malignantand malignant cellular proliferation, including but not limited to,malignant neoplasms and tumours, cancers, leukemias, psoriasis, bonediseases, fibroproliferative disorders (e.g., of connective tissues),and atherosclerosis. Any type of cell may be treated, including but notlimited to, lung, colon, breast, ovarian, prostate, liver, pancreas,brain, and skin.

The anti-proliferative effects of the compounds of the present inventionhave particular application in the treatment of human cancers by virtueof their HSF1 inhibitory properties.

The anti-cancer effect may arise through one or more mechanisms,including but not limited to, the regulation of cell proliferation, theinhibition of angiogenesis (the formation of new blood vessels), theinhibition of metastasis (the spread of a tumour from its origin), theinhibition of invasion (the spread of tumour cells into neighbouringnormal structures), or the promotion of apoptosis (programmed celldeath).

Therefore, in another aspect, the present invention provides a compound,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein for use in the treatment ofcancer.

In yet another aspect, the present invention provides the use of acompound, or a pharmaceutically acceptable salt or solvate thereof, asdefined herein in the manufacture of a medicament for use in thetreatment of cancer.

In yet another aspect, the present invention provides a method oftreating cancer in a patient in need of such treatment, said methodcomprising administering to said patient a therapeutically effectiveamount of a compound, or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition as defined herein.

The invention further provides a method of treatment of the human oranimal body, the method comprising administering to a subject in need oftreatment a therapeutically-effective amount of an active compound,preferably in the form of a pharmaceutical composition.

Routes of Administration

The compounds of the invention or pharmaceutical composition comprisingthe active compound may be administered to a subject by any convenientroute of administration, whether systemically/peripherally or topically(ie. at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g, byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., byeyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

Combination Therapies

The antiproliferative treatment defined hereinbefore may be applied as asole therapy or may involve, in addition to the compound of theinvention, conventional surgery, radiotherapy or therapy with achemotherapeutic agent or a molecularly targeted agent. Such additionaltherapy may include one or more of the following categories ofanti-tumour agents:—

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumourantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride;(iii) anti-invasion agents [for example c-Src kinase family inhibitorslike4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline(AZD0530; International Patent Application WO 01/94341),N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) andbosutinib (SKI-606), and metalloproteinase inhibitors like marimastat,inhibitors of urokinase plasminogen activator receptor function orantibodies to Heparanase];(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab[Erbitux, C225] and any growth factor or growth factor receptorantibodies disclosed by Stern et al. Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);inhibitors of the hepatocyte growth factor family; inhibitors of theinsulin growth factor family; inhibitors of the platelet-derived growthfactor family such as imatinib and/or nilotinib (AMN107); inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006),tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cellsignalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinaseinhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinaseinhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors;aurora kinase inhibitors (for example AZD1152, PH739358, VX-680,MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependentkinase inhibitors such as CDK2 and/or CDK4 inhibitors;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and forexample, a VEGF receptor tyrosine kinase inhibitor such as vandetanib(ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736),pazopanib (GW 786034) and4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(AZD2171; Example 240 within WO 00/47212), compounds such as thosedisclosed in International Patent Applications WO97/22596, WO 97/30035,WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms(for example linomide, inhibitors of integrin αvβ3 function andangiostatin)];(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054)or atrasentan;(viii) HSP90 inhibitors (for example, geldanamycin, radicicol or17-N-Allylamino-17-demethoxygeldanamycin (17AAG));(ix) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;(x) gene therapy approaches, including for example approaches to replaceaberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT(gene-directed enzyme pro-drug therapy) approaches such as those usingcytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and(xi) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

It is anticipated that the HSF1 inhibitors of the present invention areparticularly suited to combination therapy with anti-tumour agents thatinhibit HSP90 (for example, geldanamycin, radicicol or17-N-Allylamino-17-demethoxygeldanamycin (17AAG)).

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

According to this aspect of the invention there is provided acombination suitable for use in the treatment of a cancer (for example acancer involving a solid tumour) comprising a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt orsolvate thereof, and another anti-tumour agent.

According to this aspect of the invention there is provided acombination suitable for use in the treatment of a cancer (for example acancer involving a solid tumour) comprising a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt orsolvate thereof, and any one of the anti-tumour agents listed under(i)-(xi) above.

In a further aspect of the invention there is provided a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof, incombination with an anti-tumour agent selected from one listed under(i)-(xi) herein above.

Herein, where the term “combination” is used it is to be understood thatthis refers to simultaneous, separate or sequential administration. Inone aspect of the invention “combination” refers to simultaneousadministration. In another aspect of the invention “combination” refersto separate administration. In a further aspect of the invention“combination” refers to sequential administration. Where theadministration is sequential or separate, the delay in administering thesecond component should not be such as to lose the beneficial effect ofthe combination.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the invention,or a pharmaceutically acceptable salt or solvate thereof in combinationwith an anti-tumour agent selected from one listed under (i)-(xi) hereinabove, in association with a pharmaceutically acceptable diluent orcarrier.

In another aspect, the compounds of the present invention may be usedfor the treatment of other HSF1-mediated diseases or conditions, such asautoimmune and viral diseases. In the case of autoimmune diseases, thecompounds of the invention may be combined with other agents for thetreatment of autoimmune conditions, for example, steroids and otherimmunosuppressant agents. In the case of viral diseases, the compoundsof the invention may be administered with one or more additionalantiviral agents.

EXAMPLES Preparation of Compound 1,N-(4-methyl-3-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

Oxalyl chloride (1.40 mL, 16.6 mmol) was added dropwise to a solution of1,4-benzodioxane-6-carboxylic acid (2.486 g, 13.80 mmol) and DMF (0.027mL, 0.34 mmol) in dry DCM (34 mL). The reaction mixture was stirred atrt for 3.5 h, and then concentrated. The residue was dissolved in DCMand concentrated again. This residue was dissolved in dry DCM (12 mL)and added dropwise to a solution of 4-methyl-3-nitroaniline (2.100 g,13.80 mmol) and pyridine (2.23 mL, 27.6 mmol) in dry DCM (25 mL). Thereaction mixture was stirred at rt for 2 h, and then concentrated. Theresulting solid was suspended in MeOH, diluted with water and thenisolated by filtration and washed with water to afford the titlecompound (4.24 g, 98%) as a pale tan coloured solid. ¹H NMR (500 MHz,DMSO) δ 10.39 (s, 1H), 8.54 (d, J=2.2 Hz, 1H), 7.99 (dd, J=8.4, 2.3 Hz,1H), 7.55 (d, J=2.1 Hz, 1H), 7.52 (dd, J=8.4, 2.2 Hz, 1H), 7.47 (dd,J=8.4, 0.8 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 4.34-4.29 (m, 4H), 2.49 (s,3H). HRMS (ESI⁺): calcd for C₁₆H₁₅N₂O₅ (M+H)⁺, 315.0976; found 315.0982.

Preparation of Compound 2,N-(3-amino-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

Palladium (10% on activated carbon, 0.567 g) was added to a suspensionof Compound 1 (4.237 g, 13.48 mmol) in ethanol (90 mL) and ethyl acetate(90 mL). The reaction mixture was stirred under hydrogen (1 atm) at 28°C. overnight, filtered through celite with EtOAc, and concentrated, toafford the title compound (3.803 g, 99%) as a pale yellow amorphoussolid. ¹H NMR (500 MHz, DMSO) δ 9.70 (s, 1H), 7.49 (d, J=2.2 Hz, 1H),7.46 (dd, J=8.3, 2.2 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 6.95 (d, J=8.4 Hz,1H), 6.83 (d, J=8.1 Hz, 1H), 6.79 (dd, J=8.1, 2.0 Hz, 1H), 4.81 (s, 2H),4.32-4.26 (m, 4H), 2.01 (s, 3H). HRMS (ESI⁺): calcd for C₁₆H₁₇N₂O₃(M+H)⁺, 285.1234; found 285.1233.

Example 1,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide

2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU, 3.34 g, 8.79 mmol) was added to a solution of6-quinolinecarboxylic acid (1.34 g, 7.74 mmol) andN,N-diisopropylethylamine (DIEA, 2.76 mL, 15.8 mmol) in dry DMF (40 mL).The reaction mixture was stirred for 6 min, before Compound 2 was added(2.00 g, 7.03 mmol). The reaction mixture was stirred at rt overnight,diluted with water and the resulting precipitate isolated by filtration,washed with water and dried to afford the title compound (3.09 g, 100%)as an off-white solid. ¹H NMR (500 MHz, DMSO) δ 10.18 (s, 1H), 10.08 (s,1H), 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.54 (dd,J=8.4, 1.9 Hz, 1H), 8.29 (dd, J=8.8, 2.1 Hz, 1H), 8.15 (d, J=8.8 Hz,1H), 7.88 (d, J=2.2 Hz, 1H), 7.65 (dd, J=8.3, 4.2 Hz, 1H), 7.59 (dd,J=8.2, 2.2 Hz, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.51 (dd, J=8.4, 2.2 Hz,1H), 7.25 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.34-4.28 (m, 4H),2.25 (s, 3H). HRMS (ESI⁺): calcd for C₂₆H₂₂N₃O₄ (M+H)⁺, 440.1605; found440.1598.

Examples 2 to 48

The following compounds were synthesised according to the procedure forExample 1, by substituting the appropriate carboxylic acid for6-quinolinecarboxylic acid:

-   Example 2,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)isoquinoline-7-carboxamide-   Example 3,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-methoxyethoxy)quinoline-6-carboxamide-   Example 4,    N-(4-methyl-3-(2-oxo-2H-chromene-6-carboxamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 5,    N-(3-(3,4-dimethoxybenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 6,    N-(3-(2,3-dihydrobenzofuran-5-carboxamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 7,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1-methylindoline-5-carboxamide-   Example 8,    N-(4-methyl-3-(1-oxo-1,3-dihydroisobenzofuran-5-carboxamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 9,    N-(3-(chroman-6-carboxamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 10,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinazoline-6-carboxamide-   Example 11,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-4-methoxyquinoline-6-carboxamide-   Example 12,    2-chloro-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide-   Example 13,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(thiazol-4-ylmethoxy)nicotinamide-   Example 14,    N-(4-methyl-3-(2-methyl-2,3-dihydrobenzofuran-5-carboxamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 15,    N-(3-(1,3-dihydroisobenzofuran-5-carboxamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 16,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1-methyl-1H-indole-5-carboxamide-   Example 17,    N-(3-(benzofuran-5-carboxamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 18,    N-(3-(benzo[b]thiophene-5-carboxamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 19,    N-(4-methyl-3-(4-(pyridin-2-ylmethoxy)benzamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 20,    N-(4-methyl-3-(4-(thiazol-5-ylmethoxy)benzamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 21, tert-butyl    (2-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinolin-2-yl)oxy)ethyl)carbamate    Example 22,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-4-methoxy-2-(2-methoxyethoxy)quinoline-6-carboxamide-   Example 23,    6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinoline    1-oxide Example 24,    4-cyano-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide-   Example 25,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(pyridin-2-ylmethoxy)nicotinamide-   Example 26,    N-(3-(4-methoxy-3-methylbenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 27,    N-(3-(4-methoxybenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 28,    N-(3-(3-chloro-4-methoxybenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 29,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methoxyquinoline-6-carboxamide-   Example 30, tert-butyl    5-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)indoline-1-carboxylate-   Example 31, tert-butyl    6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate-   Example 32,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-morpholinoquinoline-6-carboxamide-   Example 33,    N5-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-N2-methylpyridine-2,5-dicarboxamide-   Example 34,    N-(4-methyl-3-(5,6,7,8-tetrahydronaphthalene-2-carboxamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 35, tert-butyl    (3-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinolin-2-yl)oxy)propyl)carbamate    Example 36,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoxaline-6-carboxamide-   Example 37,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-phenylnicotinamide-   Example 38,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-((3-iodophenyl)amino)nicotinamide-   Example 39,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methylquinoline-6-carboxamide-   Example 40,    N-(3-(3-methoxybenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 41,    N-(3-(4-bromo-3-methoxybenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 42,    N-(3-(4-methoxy-3,5-dimethylbenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 43,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1,6-naphthyridine-3-carboxamide-   Example 44,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1,7-naphthyridine-3-carboxamide-   Example 45,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1,8-naphthyridine-3-carboxamide-   Example 46,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)isoquinoline-6-carboxamide-   Example 47,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-3-carboxamide-   Example 48,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-carboxamide

TABLE A 1H NMR Mass Spec Example ¹H NMR (500 MHz, DMSO) δ 10.25 (s, 1H),10.08 (s, 1H), 9.57 (s, Found 2 1H), 8.86 (s, 1H), 8.65 (d, J = 5.8 Hz,1H), 8.36 (dd, J = 8.6, 1.5 Hz, [M + H]⁺ = 1H), 8.18 (d, J = 8.6 Hz,1H), 8.04 (d, J = 5.8 Hz, 1H), 7.90 (d, J = 1.9 440.1604 Hz, 1H), 7.59(dd, J = 8.3, 2.1 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.51 C26H22N3O4(dd, J = 8.4, 2.1 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4Hz, requires 1H), 4.31 (m, 4H), 2.25 (s, 3H). 440.1605 Example ¹H NMR(500 MHz, DMSO) δ 10.07 (s, 1H), 10.07 (s, 1H), 8.57 (d, J = Found 3 1.9Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.22 (dd, J = 8.7, 2.0 Hz, 1H), [M +H]⁺ = 7.86 (m, 2H), 7.58 (dd, J = 8.3, 2.1 Hz, 1H), 7.54 (d, J = 2.1 Hz,1H), 514.1969 7.51 (dd, J = 8.4, 2.2 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H),7.13 (d, J = C29H28N3O6 8.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.60-4.56(m, 2H), 4.33-4.28 requires (m, 4H), 3.78-3.70 (m, 2H), 3.33 (s, 3H),2.23 (s, 3H). 514.1973 Example ¹H NMR (500 MHz, DMSO) δ 10.08 (s, 1H),10.07 (s, 1H), 8.37 (d, J = Found 4 2.2 Hz, 1H), 8.22 (d, J = 2.1 Hz,1H), 8.19 (d, J = 9.4 Hz, 1H), 7.84 [M + H]⁺ = (d, J = 2.2 Hz, 1H),7.60-7.52 (m, 3H), 7.51 (dd, J = 8.5, 2.2 Hz, 457.1395 1H), 7.23 (d, J =8.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 9.6 C26H21N2O6 Hz,1H), 4.31 (m, 4H), 2.21 (s, 3H). requires 457.1394 Example ¹H NMR (500MHz, DMSO) δ 10.05 (s, 1H), 9.79 (s, 1H), 7.80 (d, J = Found 5 2.2 Hz,1H), 7.64 (dd, J = 8.4, 2.1 Hz, 1H), 7.58-7.55 (m, 2H), 7.53 [M + H]⁺ =(d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.4, 2.2 Hz, 1H), 7.22 (d, J = 8.5Hz, 449.1707 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H),4.35-4.26 (m, C25H25N2O6 4H), 3.84 (s, 3H), 3.84 (s, 3H), 2.19 (s, 3H).requires 449.1707 Example ¹H NMR (500 MHz, DMSO) δ 10.04 (s, 1H), 9.68(s, 1H), 7.89 (d, J = Found 6 1.9 Hz, 1H), 7.82-7.78 (m, 2H), 7.56 (dd,J = 8.2, 2.2 Hz, 1H), 7.53 [M + H]⁺ = (d, J = 2.1 Hz, 1H), 7.50 (dd, J =8.5, 2.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 431.1586 1H), 6.98 (d, J = 8.4Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 4.63 (t, J = 8.7 C25H23N2O5 Hz, 2H),4.30 (m, 4H), 3.25 (t, J = 8.7 Hz, 2H), 2.18 (s, 3H). requires 431.1602Example ¹H NMR (500 MHz, DMSO) δ 10.02 (s, 1H), 9.46 (s, 1H), 7.78 (d, J= Found 7 2.2 Hz, 1H), 7.75 (dd, J = 8.2, 1.9 Hz, 1H), 7.68 (d, J = 1.9Hz, 1H), [M + H]⁺ = 7.58-7.52 (m, 2H), 7.50 (dd, J = 8.5, 2.3 Hz, 1H),7.18 (d, J = 8.3 444.1920 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.53 (d, J= 8.2 Hz, 1H), 4.33-4.28 C26H26N3O4 (m, 4H), 3.40 (t, J = 8.3 Hz, 2H),2.96 (t, J = 8.3 Hz, 2H), 2.79 (s, 3H), requires 2.17 (s, 3H). 444.1918Example ¹H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 10.08 (s, 1H), 8.23 (s,Found 8 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.85(d, J = 2.2 [M + H]⁺ = Hz, 1H), 7.59 (dd, J = 8.2, 2.2 Hz, 1H), 7.53 (d,J = 2.1 Hz, 1H), 7.51 445.1396 (dd, J = 8.3, 2.2 Hz, 1H), 7.24 (d, J =8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, C25H21N2O6 1H), 5.51 (s, 2H),4.33-4.28 (m, 4H), 2.21 (s, 3H). requires 445.1394 Example ¹H NMR (500MHz, DMSO) δ 10.03 (s, 1H), 9.68 (s, 1H), 7.79-7.75 Found 9 (m, 2H),7.73 (dd, J = 8.5, 2.2 Hz, 1H), 7.56 (dd, J = 8.3, 2.2 Hz, 1H), [M + H]⁺= 7.53 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.4, 2.2 Hz, 1H), 7.20 (d, J =445.1753 8.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.5 Hz,1H), 4.34- C26H25N2O5 4.27 (m, 4H), 4.23-4.17 (m, 2H), 2.82 (t, J = 6.3Hz, 2H), 2.17 (s, requires 3H), 2.00-1.92 (m, 2H). 445.1758 Example ¹HNMR (500 MHz, DMSO) δ 10.31 (s, 1H), 10.09 (s, 1H), 9.79 (s, Found 101H), 9.41 (s, 1H), 8.84 (d, J = 1.9 Hz, 1H), 8.54 (dd, J = 8.8, 2.0 Hz,[M + H]⁺ = 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.59(dd, J = 441.1553 8.2, 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.51 (dd,J = 8.5, 2.2 Hz, C25H21N4O4 1H), 7.26 (d, J = 8.6 Hz, 1H), 6.98 (d, J =8.5 Hz, 1H), 4.33-4.28 (m, requires 4H), 2.25 (s, 3H). 441.1557 Example¹H NMR (500 MHz, DMSO) δ 10.25 (s, 1H), 10.07 (s, 1H), 8.87- Found 118.82 (m, 2H), 8.28 (dd, J = 8.8, 2.1 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H),[M + H]⁺ = 7.84 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 8.3, 2.2 Hz, 1H),7.54 (d, J = 470.1699 2.2 Hz, 1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.24(d, J = 8.2 Hz, 1H), C27H24N3O5 7.15 (d, J = 5.3 Hz, 1H), 6.98 (d, J =8.4 Hz, 1H), 4.33-4.28 (m, 4H), requires 4.12 (s, 3H), 2.23 (s, 3H).470.1710 Example ¹H NMR (500 MHz, DMSO) δ 10.22 (s, 1H), 10.08 (s, 1H),8.72 (d, J = Found 12 1.9 Hz, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.34 (dd, J= 8.8, 2.0 Hz, 1H), [M + H]⁺ = 8.09 (d, J = 8.8 Hz, 1H), 7.88 (d, J =2.1 Hz, 1H), 7.71 (d, J = 8.6 Hz, 474.1181 1H), 7.59 (dd, J = 8.3, 2.2Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.51 (dd, C26H21³⁵ClN3O4 J = 8.5, 2.2Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), requires4.33-4.28 (m, 4H), 2.24 (s, 3H). 474.1215 Example ¹H NMR (500 MHz, DMSO)δ 10.06 (s, 1H), 9.95 (s, 1H), 9.13 (d, J = Found 13 1.9 Hz, 1H), 8.83(dd, J = 2.4, 0.8 Hz, 1H), 8.28 (dd, J = 8.7, 2.5 Hz, [M + H]⁺ = 1H),7.83 (d, J = 2.2 Hz, 1H), 7.80-7.79 (m,, 1H), 7.57 (dd, J = 8.3,503.1380 2.2 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 8.4, 2.2Hz, 1H), C26H23N4O5S 7.22 (d, J = 8.6 Hz, 1H), 7.02 (dd, J = 8.7, 0.8Hz, 1H), 6.98 (d, J = requires 8.4 Hz, 1H), 5.56 (s, 2H), 4.33-4.28 (m,,4H), 2.20 (s, 3H). 503.1384 Example ¹H NMR (500 MHz, DMSO) δ 10.04 (s,1H), 9.67 (s, 1H), 7.87-7.85 Found 14 (m, 1H), 7.82-7.77 (m, 2H), 7.56(dd, J = 8.3, 2.2 Hz, 1H), 7.53 (d, J = [M + H]⁺ = 2.0 Hz, 1H), 7.50(dd, J = 8.4, 2.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 445.1757 6.98 (d, J= 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.06-4.98 (m, 1H), C26H25N2O54.33-4.28(m, 4H), 3.39 (dd, J = 15.8, 8.9 Hz, 1H), 2.85 (dd, J = 15.8,requires 7.4 Hz, 1H), 2.18 (s, 3H), 1.41 (d, J = 6.2 Hz, 3H). 445.1758Example ¹H NMR (500 MHz, DMSO) δ 10.06 (s, 1H), 9.91 (s, 1H), 7.94-7.89Found 15 (m, 2H), 7.82 (d, J = 2.1 Hz, 1H), 7.58 (dd, J = 8.3, 2.2 Hz,1H), 7.53 [M + H]⁺ = (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 8.4, 2.2 Hz,1H), 7.46 (d, J = 8.2 Hz, 431.1600 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.98(d, J = 8.4 Hz, 1H), 5.08 (s, 4H), C22H23N2O5 4.33-4.28 (m, 4H), 2.20(s, 3H). requires 431.1602 Example ¹H NMR (500 MHz, DMSO) δ 10.04 (s,1H), 9.76 (s, 1H), 8.29 (d, J = Found 16 1.7 Hz, 1H), 7.86-7.80 (m, 2H),7.58 (dd, J = 8.2, 2.2 Hz, 1H), 7.56- [M + H]⁺ = 7.53 (m, 2H), 7.51 (dd,J = 8.3, 2.2 Hz, 1H), 7.45 (d, J = 3.1 Hz, 442.17556 1H), 7.21 (d, J =8.3 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 3.0 C26H24N3O4 Hz,1H), 4.33-4.28 (m, 4H), 3.85 (s, 3H), 2.22 (s, 3H). requires 442.1761Example ¹H NMR (500 MHz, DMSO) δ 10.06 (s, 1H), 9.94 (s, 1H), 8.34 (d, J= Found 17 1.6 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 8.6, 1.8Hz, 1H), [M + H]⁺ = 7.84 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H),7.58 (dd, J = 8.3, 429.1435 2.2 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.51(dd, J = 8.4, 2.1 Hz, 1H), C25H21N2O5 7.22 (d, J = 8.4 Hz, 1H), 7.11(dd, J = 2.2, 0.9 Hz, 1H), 6.98 (d, J = requires 8.4 Hz, 1H), 4.33-4.28(m, 4H), 2.22 (s, 3H). 429.1445 Example ¹H NMR (500 MHz, DMSO) δ 10.07(s, 1H), 10.01 (s, 1H), 8.54 (d, J = Found 18 1.4 Hz, 1H), 8.16 (d, J =8.4 Hz, 1H), 7.96 (dd, J = 8.5, 1.7 Hz, 1H), [M + H]⁺ = 7.90 (d, J = 5.4Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.61 (dd, J = 5.5, 445.1214 0.8 Hz,1H), 7.59 (dd, J = 8.2, 2.2 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H),C25H21N2O4S 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H),6.98 (d, J = requires 8.4 Hz, 1H), 4.34-4.27 (m, 4H), 2.23 (s, 3H).445.1216 Example ¹H NMR (500 MHz, DMSO) δ 10.04 (s, 1H), 9.76 (s, 1H),8.60 (ddd, J = Found 19 4.9, 1.8, 0.9 Hz, 1H), 7.97 (d, J = 8.8 Hz, 2H),7.85 (td, J = 7.7, 1.8 [M + H]⁺ = Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H),7.59-7.52 (m, 3H), 7.50 (dd, J = 496.1867 8.5, 2.2 Hz, 1H), 7.37 (ddd, J= 7.6, 4.8, 1.2 Hz, 1H), 7.20 (d, J = 8.4 C29H26N4O5 Hz, 1H), 7.16 (d, J= 8.8 Hz, 2H), 6.98 (d, J = 8.4 Hz, 1H), 5.28 (s, requires 2H),4.33-4.28 (m, 4H), 2.18 (s, 3H). 496.1867 Example ¹H NMR (500 MHz, DMSO)δ 10.05 (s, 1H), 9.78 (s, 1H), 9.14 (d, J = Found 20 0.8 Hz, 1H), 8.06(d, J = 0.9 Hz, 1H), 7.98 (d, J = 8.8 Hz, 2H), 7.81 [M + H]⁺ = (d, J =2.2 Hz, 1H), 7.56 (dd, J = 8.2, 2.2 Hz, 1H), 7.53 (d, J = 2.1 Hz,502.1429 1H), 7.50 (dd, J = 8.5, 2.2 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H),7.17 (d, J = C27H24N3O5S 8.8 Hz, 2H), 6.98 (d, J = 8.4 Hz, 1H), 5.50 (s,2H), 4.33-4.28 (m, requires 4H), 2.19 (s, 3H). 502.1431 Example ¹H NMR(500 MHz, DMSO) δ 10.07 (s, 1H), 10.07 (s, 1H), 8.57 (d, J = Found 212.1 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.22 (dd, J = 8.8, 2.1 Hz, 1H),[M + H]⁺ = 7.86 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.58 (dd,J = 8.5, 599.2495 2.2 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.51 (dd, J =8.4, 2.2 Hz, 1H), C33H35N4O7 7.24 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 8.9Hz, 1H), 7.06 (t, J = 5.6 Hz, requires 1H), 6.98 (d, J = 8.4 Hz, 1H),4.45 (t, J = 5.7 Hz, 2H), 4.33-4.28 (m, 599.2500 2H), 3.39 (ap q, J =5.7 Hz, 2H), 2.24 (s, 3H), 1.38 (s, 9H). Example ¹H NMR (500 MHz, DMSO)δ 10.13 (s, 1H), 10.06 (s, 1H), 8.69 (d, J = Found 22 2.1 Hz, 1H), 8.21(dd, J = 8.7, 2.1 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), [M + H]⁺ = 7.79 (d,J = 8.7 Hz, 1H), 7.58 (dd, J = 8.3, 2.3 Hz, 1H), 7.54 (d, J = 554.20642.1 Hz, 1H), 7.51 (dd, J = 8.4, 2.2 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H),C30H30N3O7 6.98 (d, J = 8.4 Hz, 1H), 6.60 (s, 1H), 4.59-4.53 (m, 2H),4.33-4.28 requires (m, 4H), 3.75-3.68 (m, 2H), 3.33 (s, 3H), 2.21 (s,3H). 554.2078 Example ¹H NMR (500 MHz, DMSO) δ 10.28 (s, 1H), 10.09 (s,1H), 8.73 (d, J = Found 23 1.9 Hz, 1H), 8.69 (dd, J = 6.1, 1.0 Hz, 1H),8.64 (d, J = 9.0 Hz, 1H), [M + H]⁺ = 8.31 (dd, J = 9.1, 1.9 Hz, 1H),8.10 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 456.1553 2.2 Hz, 1H), 7.61-7.55(m, 2H), 7.54 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = C26H25N3O5 8.4, 2.2 Hz,1H), 7.25 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), requires4.33-4.28 (m, 4H), 2.24 (s, 3H). 456.1554 Example ¹H NMR (500 MHz, DMSO)δ 10.49 (s, 1H), 10.10 (s, 1H), 9.24 (d, J = Found 24 4.3 Hz, 1H), 8.77(d, J = 2.0 Hz, 1H), 8.47 (dd, J = 8.8, 2.0 Hz, 1H), [M + H]⁺ = 8.34 (d,J = 8.8 Hz, 1H), 8.27 (d, J = 4.3 Hz, 1H), 7.89 (d, J = 2.3 Hz, 465.15571H), 7.61 (dd, J = 8.3, 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.51 (dd,C27H21N4O4 J = 8.5, 2.2 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.99 (d, J =8.4 Hz, 1H), requires 4.33-4.28 (m 4H), 2.25 (s, 3H). 465.1557 Example¹H NMR (500 MHz, DMSO) δ 10.06 (s, 1H), 9.94 (s, 1H), 8.79 (dd, J =Found 25 2.5, 0.8 Hz, 1H), 8.57 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.29(dd, J = [M + H]⁺ = 8.7, 2.5 Hz, 1H), 7.85-7.79 (m, 2H), 7.57 (dd, J =8.3, 2.2 Hz, 1H), 497.1816 7.53 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 8.4,2.2 Hz, 1H), 7.48 (dt, J = C28H25N4O5 7.8, 1.0 Hz, 1H), 7.34 (ddd, J =7.6, 4.8, 1.1 Hz, 1H), 7.22 (d, J = 8.5 requires Hz, 1H), 7.09 (dd, J =8.7, 0.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.52 497.1820 (s, 2H),4.33-4.28 (m, 4H), 2.19 (s, 3H). Example ¹H NMR (500 MHz, DMSO) δ 10.04(s, 1H), 9.71 (s, 1H), 7.87 (dd, J = Found 26 8.5, 2.3 Hz, 1H), 7.82 (d,J = 2.2 Hz, 1H), 7.79 (d, J = 2.2 Hz, 1H), [M + H]⁺ = 7.56 (dd, J = 8.4,2.2 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 433.1745 8.5, 2.1Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), C25H25N2O56.98 (d, J = 8.4 Hz, 1H), 4.33-4.28 (m, 4H), 3.87 (s, 3H), 2.22 (s, 3H),requires 2.18 (s, 3H). 433.1758 Example ¹H NMR (500 MHz, DMSO) δ 10.04(s, 1H), 9.75 (s, 1H), 7.98 (d, J = Found 27 8.8 Hz, 2H), 7.80 (d, J =2.1 Hz, 1H), 7.57 (dd, J = 8.3, 2.2 Hz, 1H), [M + H]⁺ = 7.53 (d, J = 2.1Hz, 1H), 7.50 (dd, J = 8.4, 2.2 Hz, 1H), 7.21 (d, J = 419.1560 8.4 Hz,1H), 7.06 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.4 Hz, 1H), 4.34-C24H23N2O5 4.27 (m, 4H), 3.84 (s, 3H), 2.19 (s, 3H). requires 419.1602Example ¹H NMR (500 MHz, DMSO) δ 10.05 (s, 1H), 9.90 (s, 1H), 8.08 (d, J= Found 28 2.2 Hz, 1H), 7.99 (dd, J = 8.6, 2.2 Hz, 1H), 7.79 (d, J = 2.2Hz, 1H), [M + H]⁺ = 7.57 (dd, J = 8.2, 2.3 Hz, 1H), 7.53 (d, J = 2.1 Hz,1H), 7.50 (dd, J = 453.1210 8.5, 2.2 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H),7.21 (d, J = 8.3 Hz, 1H), C24H22³⁵ClN2O5 6.98 (d, J = 8.4 Hz, 1H),4.33-4.28 m, 4H), 3.95 (s, 3H), 2.18 (s, 3H). requires 453.1212 Example¹H NMR (500 MHz, DMSO) δ 10.07 (s, 1H), 10.07 (s, 1H), 8.57 (d, J =Found 29 1.9 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.23 (dd, J = 8.7, 2.0Hz, 1H), [M + H]⁺ = 7.89 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 2.1 Hz, 1H),7.58 (dd, J = 8.3, 470.1670 2.1 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.51(dd, J = 8.4, 2.2 Hz, 1H), C27H24N3O5 7.24 (d, J = 8.4 Hz, 1H), 7.12 (d,J = 8.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, requires 1H), 4.33-4.28 (m, 4H),4.03 (s, 3H), 2.24 (s, 3H). 470.1710 Example ¹H NMR (500 MHz, CDCl₃) δ8.08 (d, J = 2.2 Hz, 1H), 7.77 (s, 1H), Found 30 7.75-7.70 (m, 2H), 7.67(dd, J = 8.4, 1.9 Hz, 1H), 7.65 (s, 1H), 7.43 [M + H]⁺ = (d, J = 2.2 Hz,1H), 7.36 (dd, J = 8.4, 2.2 Hz, 1H), 7.21 (d, J = 8.1 Hz, 530.2270 1H),6.94 (d, J = 8.4 Hz, 1H), 4.33-4.28 (m, 4H), 4.05 (t, J = 8.5 Hz,C30H32N3O6 2H), 3.17 (t, J = 8.7 Hz, 2H), 2.32 (s, 3H), 1.59 (s, 9H).requires 530.2286 Example ¹H NMR (500 MHz, DMSO) δ 10.05 (s, 1H), 9.86(s, 1H), 7.82-7.78 Found 31 (m, 3H), 7.57 (dd, J = 8.3, 2.2 Hz, 1H),7.53 (d, J = 2.1 Hz, 1H), 7.50 [M + H]⁺ = (dd, J = 8.4, 2.2 Hz, 1H),7.33 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.5 Hz, 544.2376 1H), 6.98 (d, J= 8.4 Hz, 1H), 4.58 (br s, 2H), 4.33-4.28 (m, 4H), 3.59 C31H34N3O6 (t, J= 5.8 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H), 2.18 (s, 3H), 1.44 (s, 9H).requires 544.2442 Example ¹H NMR (500 MHz, DMSO) δ 10.06 (s, 1H), 9.94(s, 1H), 8.41 (d, J = Found 32 2.0 Hz, 1H), 8.19 (d, J = 9.1 Hz, 1H),8.11 (dd, J = 8.8, 2.1 Hz, 1H), [M + H]⁺ = 7.85 (d, J = 2.1 Hz, 1H),7.64 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 8.3, 525.2126 2.2 Hz, 1H), 7.54(d, J = 2.1 Hz, 1H), 7.51 (dd, J = 8.4, 2.2 Hz, 1H), C30H29N4O5 7.32 (d,J = 9.3 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, requires1H), 4.33-4.27 (m, 4H), 3.77-3.69 (m, 8H), 2.23 (s, 3H). 525.2132Example ¹H NMR (500 MHz, DMSO) δ 10.26 (s, 1H), 10.08 (s, 1H), 9.15 (s,Found 33 1H), 8.96-8.90 (m, 1H), 8.50 (dd, J = 8.1, 2.0 Hz, 1H), 8.17(d, J = 8.1 [M + H]⁺ = Hz, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.58 (dd, J =8.3, 2.1 Hz, 1H), 7.53 447.1662 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = 8.4,2.2 Hz, 1H), 7.24 (d, J = 8.5 Hz, C24H23N4O5 1H), 6.98 (d, J = 8.4 Hz,1H), 4.33-4.28 (m, 4H), 2.85 (d, J = 4.8 Hz, requires 3H), 2.22 (s, 3H).447.1663 Example ¹H NMR (500 MHz, DMSO) δ 10.04 (s, 1H), 9.78 (s, 1H),7.79 (d, J = Found 34 2.2 Hz, 1H), 7.72-7.68 (m, 2H), 7.57 (dd, J = 8.2,2.2 Hz, 1H), 7.53 [M + H]⁺ = (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.5, 2.2Hz, 1H), 7.20 (ap t, J = 7.7 443.1954 Hz, 2H), 6.98 (d, J = 8.4 Hz, 1H),4.33-4.28 (m, 4H), 2.84-2.73 (m, C27H27N2O4 4H), 2.18 (s, 3H), 1.82-1.73(m, 4H). requires 443.1965 Example ¹H NMR (500 MHz, DMSO) δ 10.07 (s,2H), 8.56 (d, J = 2.1 Hz, 1H), Found 35 8.38 (d, J = 9.0 Hz, 1H), 8.22(dd, J = 8.7, 2.1 Hz, 1H), 7.88-7.83 [M + H]⁺ = (m, 2H), 7.58 (dd, J =8.4, 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.51 613.2650 (dd, J = 8.5,2.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 8.9 Hz, C34H37N4O71H), 6.98 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 5.8 Hz, 1H), 4.45 (t, J =6.4 requires Hz, 1H), 4.33-4.28 (m, 4H), 3.16-3.09 (m, 2H), 2.23 (s,1H), 1.95-1.88 613.2657 (m, 2H), 1.37 (s, 9H). Example ¹H NMR (500 MHz,DMSO) δ 10.34 (s, 1H), 10.09 (s, 1H), 9.10- Found 36 9.05 (m, 2H), 8.78(d, J = 2.0 Hz, 1H), 8.38 (dd, J = 8.7, 2.0 Hz, 1H), [M + H]⁺ = 8.25 (d,J = 8.7 Hz, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.61 (dd, J = 8.2, 441.15522.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 8.4, 2.2 Hz, 1H),C25H21N4O4 7.26 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.33-4.28(m, 4H), requires 2.26 (s, 3H). 441.1557 Example ¹H NMR (500 MHz, DMSO)δ 10.14 (s, 1H), 10.08 (s, 1H), 9.23 (d, J = Found 37 1.7 Hz, 1H), 8.42(dd, J = 8.3, 2.2 Hz, 1H), 8.23-8.14 (m, 3H), [M + H]⁺ = 7.88 (d, J =1.9 Hz, 1H), 7.59 (dd, J = 8.3, 2.1 Hz, 1H), 7.58-7.47 466.1762 (m, 5H),7.25 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.33-4.28 C28H24N3O4(m, 4H), 2.24 (s, 3H). requires 466.1761 Example ¹H NMR (500 MHz, DMSO)δ 10.05 (s, 1H), 9.76 (s, 1H), 9.61 (s, Found 38 1H), 8.85 (d, J = 2.3Hz, 1H), 8.32 (t, J = 1.8 Hz, 1H), 8.12 (dd, J = [M + H]⁺ = 8.7, 2.4 Hz,1H), 7.83 (d, J = 2.0 Hz, 1H), 7.70-7.65 (m 1H), 7.57 (dd, 607.0833 J =8.3, 2.1 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = 8.4, 2.1C28H24IN4O4 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H),7.11 (t, J = requires 8.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.91 (d, J= 8.7 Hz, 1H), 4.34- 607.0837 4.28 (m, 4H), 2.21 (s, 3H). Example ¹H NMR(500 MHz, DMSO) δ 10.16 (s, 1H), 10.08 (s, 1H), 8.65 (s, Found 39 1H),8.51 (br d, J = 7.3 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1H), 8.06 (d, J = [M +H]⁺ = 8.8 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.64-7.56 (m, 2H), 7.54 (d,J = 454.1733 2.1 Hz, 1H), 7.51 (dd, J = 8.4, 2.2 Hz, 1H), 7.25 (d, J =8.5 Hz, 1H), C27H24N3O4 6.98 (d, J = 8.4 Hz, 1H), 4.35-4.26 (m, 4H),2.74 (s, 3H), 2.24 (s, requires 3H). 454.1761 Example ¹H NMR (500 MHz,DMSO) δ 10.06 (s, 1H), 9.91 (s, 1H), 7.81 (d, J = Found 40 2.1 Hz, 1H),7.60-7.55 (m, 2H), 7.55-7.52 (m, 2H), 7.51 (dd, J = 8.4, [M + H]⁺ = 2.2Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.16419.1606 (ddd, J = 8.2, 2.7, 1.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H),4.33-4.28 (m, C24H23N2O5 4H), 3.84 (s, 3H), 2.19 (s, 3H). requires419.1602 Example ¹H NMR (500 MHz, DMSO) δ 10.06 (s, 1H), 10.02 (s, 1H),7.83 (d, J = Found 41 2.2 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.66 (d, J= 1.9 Hz, 1H), 7.57 [M + H]⁺ = (dd, J = 8.2, 2.2 Hz, 1H), 7.55-7.48 (m,3H), 7.23 (d, J = 8.5 Hz, 497.0705 1H), 6.98 (d, J = 8.4 Hz, 1H),4.33-4.28 (m, 4H), 3.95 (s, 3H), 2.19 (s, C24H22⁷⁹BrN2O5 3H). requires497.0707 Example ¹H NMR (500 MHz, DMSO) δ 10.05 (s, 1H), 9.76 (s, 1H),7.78 (d, J = Found 42 2.2 Hz, 1H), 7.68 (s, 3H), 7.56 (dd, J = 8.2, 2.2Hz, 1H), 7.53 (d, J = [M + H]⁺ = 2.1 Hz, 1H), 7.50 (dd, J = 8.4, 2.2 Hz,1H), 7.20 (d, J = 8.4 Hz, 1H), 447.1909 6.98 (d, J = 8.4 Hz, 1H),4.33-4.28 (m, 4H), 3.71 (s, 3H), 2.30 (s, 6H), C26H27N2O5 2.17 (s, 3H).requires 447.1914 Example ¹H NMR (500 MHz, DMSO) δ 10.40 (s, 1H), 10.10(s, 1H), 9.61-9.57 Found 43 (m, 2H), 9.19 (d, J = 1.7 Hz, 1H), 8.87 (d,J = 5.9 Hz, 1H), 8.03 (d, J = [M + H]⁺ = 5.9 Hz, 1H), 7.93 (d, J = 2.2Hz, 1H), 7.59 (dd, J = 8.2, 2.2 Hz, 1H), 441.1540 7.54 (d, J = 2.2 Hz,1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.27 (d, J = C25H21N4O4 8.3 Hz,1H), 6.99 (d, J = 8.4 Hz, 1H), 4.35-4.26 (m, 4H), 2.26 (s, requires 3H).441.1557 Example ¹H NMR (500 MHz, DMSO) δ 10.43 (s, 1H), 10.10 (s, 1H),9.55- Found 44 9.47 (m, 2H), 9.05-9.00 (m, 1H), 8.74 (d, J = 5.5 Hz,1H), 8.10 (dd, [M + H]⁺ = J = 5.6, 1.0 Hz, 1H), 7.93 (d, J = 2.2 Hz,1H), 7.59 (dd, J = 8.3, 2.2 441.1559 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H),7.51 (dd, J = 8.4, 2.2 Hz, 1H), 7.26 C25H21N4O4 (d, J = 8.4 Hz, 1H),6.99 (d, J = 8.4 Hz, 1H), 4.35-4.25 (m, 4H), 2.26 requires (s, 3H).441.1557 Example ¹H NMR (500 MHz, DMSO) δ 10.36 (s, 1H), 10.10 (s, 1H),9.56 (d, J = Found 45 2.6 Hz, 1H), 9.21 (dd, J = 4.2, 2.0 Hz, 1H), 9.08(d, J = 2.6 Hz, 1H), [M + H]⁺ = 8.66 (dd, J = 8.1, 2.0 Hz, 1H), 7.92 (d,J = 2.3 Hz, 1H), 7.76 (dd, J = 441.1573 8.2, 4.2 Hz, 1H), 7.59 (dd, J =8.3, 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, C25H21N4O4 1H), 7.51 (dd, J =8.4, 2.2 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.98 (d, J = requires 8.4Hz, 1H), 4.35-4.26 (m, 4H), 2.26 (s, 3H). 441.1557 Example ¹H NMR (500MHz, DMSO-d6) δ 10.24 (s, 1H), 10.08 (s, 1H), 9.44 (s, Found 46 1H),8.67-8.55 (m, 2H), 8.28 (d, J = 8.6 Hz, 1H), 8.18 (dd, J = 8.5, [M + H]⁺= 1.5 Hz, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.59440.1589 (dd, J = 8.3, 2.2 Hz, 1H), 7.56-7.45 (m, 2H), 7.25 (d, J = 8.5Hz, C26H22N3O4 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.39-4.21 (m, 4H), 2.25(s, 3H). Requires 440.1605 Example ¹H NMR (500 MHz, DMSO-d6) δ 10.31 (s,1H), 10.10 (s, 1H), 9.40 (d, Found 47 J = 2.2 Hz, 1H), 9.00 (d, J = 1.9Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), [M + H]⁺ = 8.14 (d, J = 8.8 Hz, 1H),7.95-7.87 (m, 3H), 7.74 (ddd, J = 8.1 , 6.9, 440.1592 1.1 Hz, 2H), 7.61(dd, J = 8.3, 2.2 Hz, 1H), 7.57-7.50 (m, 2H), 7.27 C26H22N3O4 (d, J =8.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.32 (td, J = 5.1, 3.6 Hz,Requires 4H), 2.27 (s, 3H). 440.1605 Example ¹H NMR (500 MHz, DMSO-d6) δ12.00 (br s, 1H), 10.06 (s, 1H), 9.94 Found 48 (s, 1H), 8.34 (d, J = 1.8Hz, 1H), 8.10 (dd, J = 8.6, 2.0 Hz, 1H), 8.01 [M + H]⁺ = (d, J = 9.6 Hz,1H), 7.83 (d, J = 2.1 Hz, 1H), 7.57 (dd, J = 8.3, 2.2 Hz, 456.1537 1H),7.53 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.4, 2.2 Hz, 1H), 7.39 (d, J =C26H22N3O5 8.6 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.4 Hz,1H), 6.58 Requires (dd, J = 9.5, 1.9 Hz, 1H), 4.33-4.27 (m, 4H), 2.20(s, 3H). 456.1554

Preparation of Compound 3,(R)-6-bromo-2-((1-methylpyrrolidin-3-yl)oxy)quinoline

NaH (60% in mineral oil, 0.049 g, 1.24 mmol) was added to a solution of(R)-(−)-1-methyl-3-hydroxypyrrolidine (0.125 g, 1.24 mmol) in dry THF(3.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 min,then allowed to warm to rt, and stirred for 35 min before6-bromo-2-chloroquinoline (0.250 g, 1.03 mmol) was added. The reactionmixture was then heated at reflux for 5 h, cooled to rt, concentrated toremove most of the THF, diluted with water and saturated NaHCO₃(aq),extracted with DCM (3×). The combined organic phases were washed withwater (1×), dried (MgSO4), and concentrated. The crude material waspurified by silica gel column chromatography using a gradient of 2 to 5%MeOH in DCM to afford the title compound (206 mg, 65%) as a pale yellowoil. ¹H NMR (500 MHz, CDCl₃) δ 7.86 (d, J=8.9 Hz, 1H), 7.85-7.83 (m,1H), 7.68-7.64 (m, 2H), 6.92 (d, J=8.8 Hz, 1H), 5.68-5.63 (m, 1H),2.94-2.88 (m, 2H), 2.83 (dd, J=10.8, 5.9 Hz, 1H), 2.49-2.36 (m, 5H),2.08-2.01 (m, 1H). HRMS (ESI⁺): calcd for C₁₄H₁₅ ⁷⁹BrN₂O (M+H)⁺,307.0440; found 307.0447.

Preparation of Compound 4,(R)-2-((1-methylpyrrolidin-3-yl)oxy)quinoline-6-carboxylic acidhydrochloride

nBuLi (2.28 M in hexanes, 0.437 mL, 0.996 mmol) was added dropwise to asolution of Compound 3 (0.204 g, 0.664 mmol) in dry THF (2.2 mL) at −78°C. A precipitate formed which hampered efficient stirring, thusadditional THF (1.0 mL) was added. The reaction mixture was stirred at−78° C. for 40-45 min before solid CO₂ was added. The reaction mixturewas stirred for a few minutes, before being allowed to warm to rt. Waterwas added, and the reaction mixture concentrated to remove THF. Theresulting aqueous solution was washed with EtOAc (1×) and then acidifiedwith 2 M HCl to pH 2-3, and then conc to dryness to afford the titlecompound (266 mg, contains LiBr), as an off-white solid, and was used insubsequent reactions without further purification. Note: the ¹H NMRshows 2 sets of peaks for each proton which show positive NOEcorrelations indicating that these are 2 inter-converting species. ¹HNMR (500 MHz, DMSO) δ 13.11 (v br s, 1H), 11.46 (br s, 0.5H), 11.15 (brs, 0.5H), 8.61-8.58 (m, 1H), 8.50-8.46 (m, 1H), 8.19-8.14 (m, 1H),7.7-7.814 (m, 1H), 7.17-7.10 (m, 1H), 5.81-5.76 (m, 0.5H), 5.73-5.69 (m,0.5H), 4.15-4.06 (m, 0.5H), 3.80-3.74 (m, 0.5H), 3.73-3.61 (m, 1H),3.59-3.53 (m, 0.5H), 3.32-3.10 (m, 1.5H), 2.89-2.83 (m, 3H), 2.74-2.62(m, 0.5H), 2.50-2.40 (m, 0.5H), 2.38-2.28 (m, 0.5H), 2.26-2.15 (m,0.5H). HRMS (ESI⁺): calcd for C₁₅H₁₇N₂O₃ (M+H)⁺, 273.1234; found273.1234.

Example 49,(R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((1-methylpyrrolidin-3-yl)oxy)quinoline-6-carboxamide

2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU, 0.111 g, 0.293 mmol) was added to a solutionof Compound 4 (0.086 g, 0.23 mmol) and N,N-diisopropylethylamine (0.17mL, 1.0 mmol) in dry DMF (1.7 mL). The reaction mixture was stirred for4 min, before Compound 2 (0.050 g, 0.18 mmol) was added. The reactionmixture was stirred at rt overnight, diluted with water and theresulting precipitate isolated by filtration, washed with water, anddried. The crude material was purified by silica gel columnchromatography using a gradient of 5 to 12% MeOH in DCM to afford thetitle compound (73 mg, 77%) as a white solid. ¹H NMR (500 MHz, DMSO) δ10.07 (s, 1H), 10.07 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.38 (d, J=8.9 Hz,1H), 8.23 (dd, J=8.8, 2.1 Hz, 1H), 7.88-7.83 (m, 2H), 7.58 (dd, J=8.2,2.2 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.51 (dd, J=8.4, 2.2 Hz, 1H), 7.24(d, J=8.4 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H),5.65-5.58 (m, 1H), 4.35-4.26 (m, 4H), 2.99-2.94 (m, 1H), 2.84-2.77 (m,2H), 2.50-2.36 (m, 2H), 2.35 (s, 3H), 2.23 (s, 3H), 1.98-1.87 (m, 1H).HRMS (ESI⁺): calcd for C₃₁H₃₁N₄O₅ (M+H)⁺, 539.2289; found 539.2285.

Examples 50 to 74

The following compounds were prepared as for Example 49 by substitutingthe appropriate carboxylic acid compound for Compound 4.

-   Example 50,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((1-methylpiperidin-4-yl)oxy)quinoline-6-carboxamide-   Example 51,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(3-(dimethylamino)propoxy)quinoline-6-carboxamide-   Example 52,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(3-(piperidin-1-yl)propoxy)quinoline-6-carboxamide-   Example 53,    (S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((1-methylpyrrolidin-2-yl)methoxy)quinoline-6-carboxamide-   Example 54,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(piperidin-1-yl)ethoxy)quinoline-6-carboxamide-   Example 55,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(3-morpholinopropoxy)quinoline-6-carboxamide-   Example 56,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(3-(pyrrolidin-1-yl)propoxy)quinoline-6-carboxamide-   Example 57,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(3-fluoropiperidin-1-yl)ethoxy)quinoline-6-carboxamide-   Example 58,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((2-(dimethylamino)ethyl)(methyl)amino)quinoline-6-carboxamide-   Example 59,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(pyrrolidin-1-yl)ethyl)quinoline-6-carboxamide-   Example 60,    2-(2-(azetidin-1-yl)ethoxy)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide-   Example 61,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(2-methylpyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide-   Example 62,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(dimethylamino)ethoxy)quinoline-6-carboxamide-   Example 63,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide-   Example 64,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)quinoline-6-carboxamide-   Example 65,    (S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(3-fluoropyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide-   Example 66,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-morpholinoethoxy)quinoline-6-carboxamide-   Example 67,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(pyrrolidin-1-ylmethyl)quinoline-6-carboxamide    formate Example 68,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(pyrrolidin-1-yl)propoxy)quinoline-6-carboxamide-   Example 69,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(dimethylamino)ethyl)quinoline-6-carboxamide-   Example 70,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((4-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide-   Example 71,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((dimethylamino)methyl)quinoline-6-carboxamide-   Example 72,    2-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide-   Example 73,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((1-(pyrrolidin-1-yl)propan-2-yl)oxy)quinoline-6-carboxamide-   Example 74,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(4-methylpiperazin-1-yl)quinoline-6-carboxamide

TABLE B 1H NMR Mass Spec Example ¹H NMR (500 MHz, DMSO) δ 10.07 (s, 2H),8.56 (d, J = 2.1 Hz, 1H), Found 50 8.37 (d, J = 8.8 Hz, 1H), 8.22 (dd, J= 8.7, 2.1 Hz, 1H), 7.86 (d, J = [M + H]⁺ = 2.1 Hz, 1H), 7.84 (d, J =8.7 Hz, 1H), 7.58 (dd, J = 8.3, 2.2 Hz, 1H), 553.2443 7.54 (d, J = 2.1Hz, 1H), 7.51 (dd, J = 8.4, 2.2 Hz, 1H), 7.24 (d, J = C32H32N4O5 8.3 Hz,1H), 7.08 (d, J = 8.9 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.35- requires5.27 (m, 1H), 4.34-4.26 (m, 4H), 2.78 (br s, 2H), 2.38 (br s, 2H),553.2446 2.30 (br s, 2H), 2.23 (s, 3H), 2.14-2.06 (m, 2H), 1.85-1.76 (m,2H). Example ¹H NMR (500 MHz, DMSO) δ 10.07 (s, 2H), 8.56 (d, J = 2.0Hz, 1H), Found 51 8.37 (d, J = 8.8 Hz, 1H), 8.22 (dd, J = 8.7, 2.0 Hz,1H), 7.88-7.84 (m, [M + H]⁺ = 2H), 7.58 (dd, J = 8.3, 2.2 Hz, 1H), 7.54(d, J = 2.1 Hz, 1H), 7.51 (dd, 541.24423 J = 8.4, 2.2 Hz, 1H), 7.24 (d,J = 8.5 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), C31H33N4O5 6.98 (d, J = 8.4Hz, 1H), 4.47 (t, J = 6.7 Hz, 2H), 4.34-4.27 (m, 4H), requires 2.39 (t,J = 7.1 Hz, 2H), 2.24 (s, 3H), 2.17 (s, 6H), 1.93 (p, J = 6.8 Hz,541.2446 2H). Example ¹H NMR (500 MHz, DMSO) δ 10.07 (s, 2H), 8.57 (d, J= 2.1 Hz, 1H), Found 52 8.38 (d, J = 8.9 Hz, 1H), 8.23 (dd, J = 8.8, 2.1Hz, 1H), 7.89-7.83 [M + H]⁺ = (m, 2H), 7.58 (dd, J = 8.3, 2.1 Hz, 1H),7.54 (d, J = 2.1 Hz, 1H), 7.51 581.2759 (dd, J = 8.5, 2.2 Hz, 1H), 7.24(d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, C34H37N4O5 1H), 6.98 (d, J =8.4 Hz, 1H), 4.49 (t, J = 6.5 Hz, 2H), 4.34-4.26 (m, requires 4H),2.70-2.30 (m, 6H), 2.24 s, 3H), 2.02 (br s, 2H), 1.56 (br s, 4H),581.2758 1.42 (br s, 2H). Example ¹H NMR (500 MHz, DMSO) δ 10.07 (s,1H), 10.07 (s, 1H), 8.57 (d, J = Found 53 1.9 Hz, 1H), 8.39 (d, J = 8.9Hz, 1H), 8.23 (dd, J = 8.7, 2.0 Hz, 1H), [M + H]⁺ = 7.89-7.85 (m, 2H),7.58 (dd, J = 8.3, 2.1 Hz, 1H), 7.54 (d, J = 2.1 Hz, 553.2448 1H), 7.51(dd, J = 8.5, 2.2 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.12 (d, J =C32H33N4O5 8.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.49 (dd, J = 10.9,5.3 Hz, requires 1H), 4.40 (br s, 1H), 4.34-4.26 (m, 4H), 3.05 (br s,1H), 2.78 (br s, 553.2446 1H), 2.47 (br s, 3H), 2.37-2.26 (m, 1H), 2.24(s, 3H), 2.07-1.98 (m, 1H), 1.78-1.66 (m, 3H). Example ¹H NMR (500 MHz,DMSO) δ 10.07 (s, 2H), 8.57 (d, J = 1.9 Hz, 1H), Found 54 8.38 (d, J =8.9 Hz, 1H), 8.22 (dd, J = 8.7, 2.0 Hz, 1H), 7.88-7.84 [M + H]⁺ = (m,2H), 7.58 (dd, J = 8.3, 2.2 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.51567.2598 (dd, J = 8.4, 2.2 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.11 (d, J= 8.8 Hz, C33H35N4O5 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.60-4.54 (m, 1H),4.34-4.27 (m, 4H), requires 2.75 (br s, 1H), 2.61-2.36 (br s, 4H), 2.24(s, 3H), 1.51 (br s, 4H), 567.2602 1.39 (brs, 2H). Example ¹H NMR (500MHz, DMSO) δ 10.07 (s, 2H), 8.56 (d, J = 2.1 Hz, 1H), Found 55 8.37 (d,J = 8.9 Hz, 1H), 8.22 (dd, J = 8.7, 2.0 Hz, 1H), 7.88-7.83 [M + H]⁺ =(m, 2H), 7.58 (dd, J = 8.4, 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.51583.2586 (dd, J = 8.5, 2.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.10 (d, J= 8.8 Hz, C33H35N4O6 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.49 (t, J = 6.6 Hz,2H), 4.34-4.27 (m, requires 4H), 3.59 (t, J = 4.7 Hz, 4H), 2.50-2.44 (m,2H), 2.39 (br s, 4H), 2.24 583.2551 (s, 3H), 1.97 (p, J = 6.7 Hz, 2H).Example ¹H NMR (500 MHz, DMSO) δ 10.07 (s, 2H), 8.57 (d, J = 2.0 Hz,1H), Found 56 8.38 (d, J = 8.8 Hz, 1H), 8.22 (dd, J = 8.8, 2.1 Hz, 1H),7.88-7.84 [M + H]⁺ = (m, 2H), 7.58 (dd, J = 8.3, 2.2 Hz, 1H), 7.54 (d, J= 2.2 Hz, 1H), 7.51 567.2594 (dd, J = 8.5, 2.2 Hz, 1H), 7.24 (d, J = 8.3Hz, 1H), 7.10 (d, J = 8.8 Hz, C33H35N4O5 1H), 6.98 (d, J = 8.4 Hz, 1H),4.49 (t, J = 6.6 Hz, 2H), 4.33-4.28 (m, requires 4H), 2.65 (br s, 2H),2.54 (br s, 4H), 2.23 (s, 3H), 1.99 (p, J = 6.8 Hz, 567.2602 2H), 1.72(br s, 4H). Example ¹H NMR (500 MHz, DMSO) δ 10.07 (s, 2H), 8.57 (d, J =2.0 Hz, 1H), Found 57 8.38 (d, J = 8.9 Hz, 1H), 8.22 (dd, J = 8.7, 2.0Hz, 1H), 7.88-7.84 (m, [M + H]⁺ = 2H), 7.58 (dd, J = 8.2, 2.2 Hz, 1H),7.54 (d, J = 2.1 Hz, 1H), 7.51 (dd, 585.2505 J = 8.4, 2.1 Hz, 1H), 7.24(d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), C33H34FN4O5 6.98 (d, J =8.4 Hz, 1H), 4.69-4.52 (m, 3H), 4.35-4.26 (m, 4H), requires 2.93-2.84(m, 1H), 2.84-2.80 (m, 2H), 2.61-2.53 (m, 1H), 2.50- 585.2509 2.45 (m,1H), 2.41-2.34 (m, 1H), 2.24 (s, 3H), 1.88-1.76 (m, 1H), 1.74-1.66 (m,1H), 1.55-1.40 (m, 2H). Example ¹H NMR (500 MHz, DMSO) δ 10.06 (s, 1H),9.91 (s, 1H), 8.38 (d, J = Found 58 2.1 Hz, 1H), 8.12 (d, J = 9.2 Hz,1H), 8.08 (dd, J = 8.7, 2.1 Hz, 1H), [M + H]⁺ = 7.85 (d, J = 2.2 Hz,1H), 7.60-7.56 (m, 2H), 7.54 (d, J = 2.1 Hz, 1H), 540.2604 7.51 (dd, J =8.4, 2.2 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.14 (d, J = C31H34N5O4 9.2Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.34-4.27 (m, 4H), 3.82 (t, J =requires 6.6 Hz, 2H), 3.18 (s, 3H), 2.59 (br s, 2H), 2.30 (br s, 6H),2.23 (s, 3H). 540.2605 Example ¹H NMR (500 MHz, DMSO) δ 10.14 (s, 1H),10.07 (s, 1H), 8.62 (d, J = Found 59 2.0 Hz, 1H), 8.44 (d, J = 8.5 Hz,1H), 8.25 (dd, J = 8.8, 2.0 Hz, 1H), [M + H]⁺ = 8.06 (d, J = 8.8 Hz,1H), 7.88 (d, J = 2.2 Hz, 1H), 7.61-7.57 (m, 2H), 537.2498 7.54 (d, J =2.2 Hz, 1H), 7.51 (dd, J = 8.3, 2.2 Hz, 1H), 7.24 (d, J = C32H33N4O4 8.3Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.33-4.28 (m, 4H), 3.22-3.14 requires(m, 2H), 3.02 (bt s, 2H), 2.64 (bt s, 4H), 2.24 (s, 3H), 1.72 (bt s,4H). 537.2496 Example ¹H NMR (500 MHz, DMSO) δ 10.08 (s, 1H), 10.07 (s,1H), 8.57 (d, J = Found 60 2.0 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.22(dd, J = 8.7, 2.0 Hz, 1H), [M + H]⁺ = 7.89-7.83 (m, 2H), 7.58 (dd, J =8.3, 2.2 Hz, 1H), 7.54 (d, J = 2.1 539.2289 Hz, 1H), 7.51 (dd, J = 8.4,2.1 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.10 C31H31N4O5 (d, J = 8.8 Hz,1H), 6.98 (d, J = 8.4 Hz, 1H), 4.43 (t, J = 5.6 Hz, 2H), requires4.34-4.27 (m, 4H), 3.40-3.30 (m, 4H), 2.94-2.88 (m, 2H), 2.23 (s, 3H),539.2289 2.03 (p, J = 7.1 Hz, 2H). Example ¹H NMR (500 MHz, DMSO) δ10.08 (s, 2H), 8.57 (d, J = 2.1 Hz, 1H), Found 61 8.38 (d, J = 8.9 Hz,1H), 8.23 (dd, J = 8.8, 2.1 Hz, 1H), 7.89-7.83 [M + H]⁺ = (m, 2H), 7.58(dd, J = 8.3, 2.2 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.51 567.2597 (dd,J = 8.4, 2.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.8 Hz,C33H35N4O5 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.61-4.52 (m, 2H), 4.33-4.28(m, 4H), requires 3.21 (br s, 2H), 2.54 (br s, 1H), 2.40 (br s, 1H),2.25 (br s, 1H), 2.24 567.2602 (s, 3H), 1.89 (br s, 1H), 1.68 (br s,2H), 1.31 (br s, 1H), 1.07 (br s, 3H). Example ¹H NMR (500 MHz, DMSO) δ10.10 (s, 1H), 10.07 (s, 1H), 8.60 (d, J = Found 62 1.9 Hz, 1H), 8.44(d, J = 8.9 Hz, 1H), 8.26 (dd, J = 8.7, 2.0 Hz, 1H), [M + H]⁺ =7.92-7.86 (m, 2H), 7.56 (dd, J = 8.3, 2.2 Hz, 1H), 7.53 (d, J = 2.1527.2285 Hz, 1H), 7.51 (dd, J = 8.4, 2.2 Hz, 1H), 7.24 (d, J = 8.5 Hz,1H), 7.15 C30H31N4O5 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H),4.77-4.72 (m, 2H), 4.34- requires 4.27 (m, 4H), 3.39 (br s, 2H), 2.76(br s, 6H), 2.24 (s, 3H). 527.2289 Example ¹H NMR (500 MHz, DMSO) δ10.07 (s, 2H), 8.57 (d, J = 2.0 Hz, 1H), Found 63 8.38 (d, J = 8.8 Hz,1H), 8.22 (dd, J = 8.7, 2.0 Hz, 1H), 7.88-7.84 (m, [M + H]⁺ = 2H), 7.58(dd, J = 8.3, 2.2 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.51 (dd, 553.2467J = 8.5, 2.2 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 8.8 Hz,1H), C32H33N4O5 6.98 (d, J = 8.4 Hz, 1H), 4.57 (t, J = 5.8 Hz, 2H),4.34-4.27 (m, 4H), requires 2.89 (br s, 2H), 2.58 (br s, 4H), 2.24 (s,3H), 1.70 (br s, 4H). 553.2446 Example ¹H NMR (500 MHz, DMSO) δ 10.06(s, 1H), 9.89 (s, 1H), 8.37 (d, J = Found 64 2.1 Hz, 1H), 8.11 (d, J =9.2 Hz, 1H), 8.08 (dd, J = 8.7, 2.1 Hz, 1H), [M + H]⁺ = 7.85 (d, J = 2.1Hz, 1H), 7.59-7.56 (m, 2H), 7.54 (d, J = 2.1 Hz, 1H), 566.2759 7.51 (dd,J = 8.4, 2.2 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.14 (d, J = C33H36N5O49.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.34-4.28 (m, 4H), 3.80 (t, J =requires 7.0 Hz, 2H), 3.20 (s, 3H), 2.68 (t, J = 6.9 Hz, 2H), 2.54 (brs, 4H), 566.2762 2.23 (s, 3H), 1.72-1.63 (m, 4H). Example ¹H NMR (500MHz, DMSO) δ 10.08 (s, 1H), 10.07 (s, 1H), 8.57 (d, J = Found 65 2.0 Hz,1H), 8.38 (d, J = 8.7 Hz, 1H), 8.22 (dd, J = 8.7, 2.1 Hz, 1H), [M + H]⁺= 7.89-7.84 (m, 2H), 7.58 (dd, J = 8.3, 2.2 Hz, 1H), 7.54 (d, J = 2.2571.2349 Hz, 1H), 7.51 (dd, J = 8.4, 2.2 Hz, 1H), 7.24 (d, J = 8.5 Hz,1H), 7.12 C32H32FN4O5 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H),5.28-5.11 (m, 1H), requires 4.60-4.53 (m, 2H), 4.34-4.27 (m, 4H),2.99-2.84 (m, 4H), 2.72 571.2351 (ddd, J = 31.6, 11.6, 5.0 Hz, 1H),2.46-2.39 (m, 1H), 2.23 (s, 3H), 2.20-2.05 (m, 1H), 1.94-1.79 (m, 1H).Example ¹H NMR (500 MHz, DMSO) δ 10.07 (s, 2H), 8.57 (d, J = 2.0 Hz,1H), Found 66 8.38 (d, J = 8.7 Hz, 1H), 8.22 (dd, J = 8.7, 2.0 Hz, 1H),7.88-7.84 [M + H]⁺ = (m, 2H), 7.58 (dd, J = 8.3, 2.2 Hz, 1H), 7.54 (d, J= 2.1 Hz, 1H), 7.51 569.2392 (dd, J = 8.4, 2.2 Hz, 1H), 7.24 (d, J = 8.5Hz, 1H), 7.12 (d, J = 8.8 Hz, C32H33N4O6 1H), 6.98 (d, J = 8.4 Hz, 1H),4.58 (t, J = 5.8 Hz, 2H), 4.34-4.27 (m, requires 4H), 3.61-3.54 (m, 4H),2.77 (t, J = 5.8 Hz, 2H), 2.24 (s, 3H). 569.2395 Example ¹H NMR (500MHz, DMSO) δ 10.15 (s, 1H), 10.08 (s, 1H), 8.63 (d, J = Found 67 2.0 Hz,1H), 8.48 (d, J = 8.5 Hz, 1H), 8.26 (dd, J = 8.8, 2.1 Hz, 1H), [M + H]⁺= 8.16 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.72523.2363 (d, J = 8.5 Hz, 1H), 7.59 (dd, J = 8.2, 2.2 Hz, 1H), 7.54 (d, J= 2.1 Hz, C31H31N4O4 1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.25 (d, J =8.4 Hz, 1H), 6.98 (d, J = requires 8.4 Hz, 1H), 4.34-4.27 (m, 4H), 3.94(s, 2H), 2.61-2.52 (m, 4H), 523.2340 2.25 (s, 3H), 1.77-1.73 (m,, 4H).Example ¹H NMR (500 MHz, DMSO) δ 10.08 (s, 1H), 10.07 (s, 1H), 8.57 (d,J = Found 68 2.0 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.23 (dd, J = 8.8,2.1 Hz, 1H), [M + H]⁺ = 7.88-7.84 (m, 2H), 7.58 (dd, J = 8.3, 2.2 Hz,1H), 7.54 (d, J = 2.1 Hz, 567.2597 1H), 7.51 (dd, J = 8.4, 2.2 Hz, 1H),7.24 (d, J = 8.4 Hz, 1H), 7.13 (d, J = C33H35N4O5 8.8 Hz, 1H), 6.98 (d,J = 8.4 Hz, 1H), 4.58 (dd, J = 11.0, 4.8 Hz, requires 1H), 4.37 (br s,1H), 4.35-4.25 (m, 4H), 2.67 (br s, 4H), 2.23 (s, 3H), 567.2602 1.71 (brs, 4H), 1.25-1.17 (m, 3H). Example ¹H NMR (500 MHz, DMSO) δ 10.18 (s,1H), 10.08 (s, 1H), 8.66 (d, J = Found 69 1.8 Hz, 1H), 8.52 (d, J = 8.4Hz, 1H), 8.30 (dd, J = 8.8, 1.9 Hz, 1H), [M + H]⁺ = 8.12 (d, J = 8.8 Hz,1H), 7.90 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 511.2341 1H), 7.56(dd, J = 8.3, 2.1 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.51 (dd,C30H31N4O4 J = 8.4, 2.2 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 6.98 (d, J =8.4 Hz, 1H), requires 4.34-4.28 (m, 4H), 3.64-3.53 (m, 2H), 3.42 (t, J =7.3 Hz, 2H), 2.86 (s, 511.2340 6H), 2.24 (s, 3H). Example ¹H NMR (500MHz, DMSO) δ 10.15 (s, 1H), 10.07 (s, 1H), 8.63 (d, J = Found 70 2.0 Hz,1H), 8.48 (d, J = 8.6 Hz, 1H), 8.26 (dd, J = 8.8, 2.0 Hz, 1H), [M + H]⁺= 8.08 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 8.5Hz, 552.2591 1H), 7.59 (dd, J = 8.2, 2.2 Hz, 1H), 7.54 (d, J = 2.1 Hz,1H), 7.51 (dd, C32H35N5O4 J = 8.5, 2.2 Hz, 1H), 7.25 (d, J = 8.3 Hz,1H), 6.98 (d, J = 8.4 Hz, 1H), requires 4.3-4.28 (m, 4H), 3.79 (s, 2H),2.48 (br s, 4H), 2.36 (br s, 4H), 2.24 552.2605 (s, 3H), 2.17 (s, 3H).Example ¹H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 10.08 (s, 1H), 8.64 (d,J = Found 71 1.9 Hz, 1H), 8.49 (d, J = 8.5 Hz, 1H), 8.26 (dd, J = 8.8,2.0 Hz, 1H), [M + H]⁺ = 8.08 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 2.1 Hz,1H), 7.72 (d, J = 8.5 Hz, 497.2183 1H), 7.59 (dd, J = 8.3, 2.2 Hz, 1H),7.54 (d, J = 2.1 Hz, 1H), 7.51 (dd, C29H29N4O4 J = 8.4, 2.2 Hz, 1H),7.25 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), requires 4.34-4.27(m, 4H), 3.74 (s, 2H), 2.26 (s, 6H), 2.25 (s, 3H). 497.2183 Example ¹HNMR (500 MHz, DMSO) δ 10.07 (s, 2H), 8.57 (d, J = 2.1 Hz, 1H), Found 728.38 (d, J = 8.8 Hz, 1H), 8.22 (dd, J = 8.7, 2.0 Hz, 1H), 7.88-7.84 (m,[M + H]⁺ = 2H), 7.58 (dd, J = 8.3, 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz,1H), 7.51 (dd, 603.2416 J = 8.5, 2.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H),7.11 (d, J = 8.8 Hz, 1H), C33H33F2N4O5 6.98 (d, J = 8.4 Hz, 1H), 4.58(t, J = 5.8 Hz, 1H), 4.34-4.27 (m, 4H), requires 2.86 (t, J = 5.8 Hz,2H), 2.65 (t, J = 5.7 Hz, 4H), 2.24 (s, 3H), 1.95 (tt, 603.2414 J =14.0, 5.6 Hz, 4H). Example ¹H NMR (500 MHz, DMSO) δ 10.07 (s, 2H), 8.56(d, J = 2.1 Hz, 1H), Found 73 8.37 (d, J = 8.9 Hz, 1H), 8.22 (dd, J =8.8, 2.1 Hz, 1H), 7.87 (d, J = [M + H]⁺ = 2.2 Hz, 1H), 7.84 (d, J = 8.7Hz, 1H), 7.58 (dd, J = 8.3, 2.2 Hz, 1H), 567.2589 7.54 (d, J = 2.2 Hz,1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.24 (d, J = C33H35N4O5 8.3 Hz,1H), 7.06 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.68- requires5.57 (m, 1H), 4.33-4.28 m, 4H), 2.88 (br s, 1H), 2.74 (br s, 1H), 2.64567.2602 (br s, 4 H), 2.23 (s, 3H), 1.68 (br s, 4H), 1.37 (d, J = 6.3Hz, 3H). Example ¹H NMR (500 MHz, CDCl₃) δ 8.18 (d, J = 1.8 Hz, 1H),8.00-7.92 (m, Found 74 2H), 7.78 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.56 (dd, J = [M + H]⁺ = 8.2, 2.1 Hz, 1H), 7.43 (d, J = 2.0 Hz,1H), 7.39 (dd, J = 8.4, 2.1 Hz, 538.2430 1H), 7.19 (d, J = 8.3 Hz, 1H),7.01 (d, J = 9.2 Hz, 1H), 6.88 (d, J = 8.4 C31H32N5O Hz, 1H), 4.30-4.22(m, 4H), 3.80 (br s, 4H), 2.59-2.51 (m, 4H), 4 requires 2.34 (s, 3H),2.28 (s, 3H). 538.2449

Preparation of Compound 5,¹ ethyl 2-(6-bromoquinolin-2-yl)acetate

nBuLi (1.84 M in hexanes, 7.54 mL, 13.9 mmol) was added dropwise to asolution of diisopropylamine (2.02 mL, 14.3 mmol) in dry diethyl ether(15 mL) at −78° C. The reaction mixture was stirred for 35 min at −78°C., before a solution of 6-bromo-2-methylquinoline (1.00 g, 4.50 mmol)in dry ether (15 mL) was added dropwise. This solution was stirred at−78° C. for 35 min, before ethyl chloroformate (0.495 mL, 5.18 mmol) indry ether (3.75 mL) was added dropwise. The reaction mixture was stirredat −78° C. for 15 min, before quenching with water (4 mL). The reactionmixture was then allowed to warm to rt, diluted with EtOAc, washed withsaturated NaHCO₃(aq) (2×), brine (1×), dried (MgSO₄), filtered andconcentrated to a volume of several mLs. This slurry was diluted with anequal volume of heptane and the mixture stood in the fridge for 2 days.The solids were then isolated by filtration, washed with coldheptane:EtOAc (2:1). An additional amount of solid was isolated fromthis filtrate. This afforded the title compound (1.014 g, 77%) as alight orange solid. ¹H NMR (500 MHz, CDCl₃) δ 8.05 (d, J=8.5 Hz, 1H),7.97 (d, J=2.2 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 7.77 (dd, J=9.0, 2.2 Hz,1H), 7.46 (d, J=8.5 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 4.02 (s, 2H), 1.27(t, J=7.1 Hz, 2H). HRMS (ESI⁺): calcd for C₁₃H₁₃ ⁷⁹BrNO₂ (M+H)⁺,294.0124; found 294.0126.

Preparation of Compound 6,¹ 2-(6-bromoquinolin-2-yl)ethanol

Ethanol (1.97 mL, 33.8 mmol) was added dropwise to solution of Compound5 (0.993 g, 3.38 mmol) and lithium borohydride (0.147 g, 6.75 mmol) indry THF (37.5 mL) at rt. The reaction mixture was stirred at rt for 5hrs, then quenched by the slow addition of MeOH (3.5 mL), concentrated,diluted with EtOAc, washed with saturade NaHCO₃(aq) (1×), water (1×),brine (1×), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by silica gel column chromatography using agradient of 50 to 60% EtOAc in PE to afford the title compound (663 mg,78%) as a light tan coloured solid. ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d,J=8.4 Hz, 1H), 7.96 (d, J=2.2 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.76 (dd,J=8.9, 2.2 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 4.46 (br s, 1H), 4.15 (t,J=5.4 Hz, 2H), 3.19 (t, J=5.4 Hz, 2H). HRMS (ESI⁺): calcd for C₁₁H₁₁⁷⁹BrNO (M+H)⁺, 252.0018; found 252.0019.

Preparation of Compound 7,6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)quinoline

To a solution of imidazole (0.122 g, 1.78 mmol) in dry DCM (7 mL) wasadded Compound 6 (0.300 g, 1.19 mmol) followed bytert-butyldimethylsilyl chloride (0.206 g, 1.37 mmol). The reactionmixture was stirred at rt for 70 min, washed with water (1×), 0.25 M HCl(1×), brine (1×), dried (MgSO₄), filtered and concentrated to afford thetitle compound (440 mg, 100%) as an off-white solid. ¹H NMR (500 MHz,DMSO) δ 8.49 (br s, 1H), 8.36 (br s, 1H), 8.01 (br d, J=9.1 Hz 1H), 7.96(br d, J=8.6 Hz, 1H), 7.69 (br d, J=7.5 Hz, 1H), 4.06 (t, J=6.3 Hz, 2H),3.19 (t, J=6.1 Hz, 2H), 0.74 (s, 9H), −0.10 (s, 6H). HRMS (ESI⁺): calcdfor C₁₇H₂₅ ⁷⁹BrNOSi (M+H)⁺, 366.0883; found 366.0883.

Preparation of Compound 8,2-(2-((tert-butyldimethylsilyl)oxy)ethyl)quinoline-6-carboxylic acid

To a suspension of Compound 7 (0.424 g, 1.16 mmol) in dry THF (8 mL) at−78° C. was added dropwise nBuLi (1.84 M in hexanes, 0.755 mL, 1.39mmol). The reaction mixture was stirred at −78° C. for 40 min beforesolid CO₂ was added. The reaction mixture was stirred at −78° C. for 15min, then allowed to warm to rt, concentrated, diluted with water,washed with DCM (2×). The aqueous phase was acidified to pH 3 with 2 MHCl, then extracted with DCM (2×). The initial DCM washes were thenadded to the aqueous phase, and after shaking, the pH of the aqueousphase was re-adjusted to 3. The layers were separated and the aqueousphase was extracted once more with DCM. The combined org phases weredried (MgSO₄), filtered, and concentrated, and the resulting crudematerial was purified by silica gel column chromatography using agradient of 25 to 33% EtOAc in PE plus 0.5% acetic acid to afford thetitle compound (66 mg, 17%) as a pale yellow solid. ¹H NMR (500 MHz,CDCl₃) δ 8.66 (d, J=1.7 Hz, 1H), 8.35 (dd, J=8.8, 1.9 Hz, 1H), 8.20 (d,J=8.4 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 4.12 (t,J=6.3 Hz, 2H), 3.24 (t, J=6.3 Hz, 2H), 0.83 (s, 9H), −0.05 (s, 6H). HRMS(ESI⁺): calcd for C₁₈H₂₆NO₃Si (M+H)⁺, 322.1676; found 322.1676.

Example 75,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-hydroxyethyl)quinoline-6-carboxamide

HATU (0.079 g, 0.21 mmol) was added to a solution of Compound 8 (0.060mg, 0.18 mmol) and N,N-diisopropylethylamine (0.064 mL, 0.36 mmol) indry DMF (1.2 mL). R^(x)n mix stirred for 4 min, before Compound 2 (0.047g, 0.16 mmol) was added. The reaction mixture was stirred at rtovernight, diluted with water and the resulting precipitate was isolatedby filtration, washed with water and dried. To 93 mg (0.16 mmol) of thisintermediate in dry THF (4 mL), tetrabutylammonium fluoride (1 M in THF,0.233 mL, 0.233 mmol) was added dropwise and the reaction mixture wasstirred at rt for 5 hrs, diluted with water and the resultingprecipitate was isolated by filtration, washed with water and dried toafford the title compound (58 mg, 74%) as a white solid. ¹H NMR (500MHz, DMSO) δ 10.14 (s, 1H), 10.07 (s, 1H), 8.62 (d, J=1.7 Hz, 1H), 8.42(d, J=8.5 Hz, 1H), 8.25 (dd, J=8.8, 1.9 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H),7.88 (d, J=1.9 Hz, 1H), 7.61-7.55 (m, 2H), 7.54 (d, J=2.0 Hz, 1H), 7.51(dd, J=8.4, 2.1 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H),4.75 (t, J=5.2 Hz, 1H), 4.35-4.27 (m, 4H), 3.89 (q, J=6.5 Hz, 2H), 3.12(t, J=6.7 Hz, 2H), 2.25 (s, 3H). HRMS (ESI⁺): calcd for C₂₈H₂₆N₃O₅(M+H)⁺, 484.1867; found 484.1868.

Preparation of Compound 9, tert-butyl(3-((6-bromoquinolin-2-yl)oxy)propyl) (methyl)carbamate

Di-tert-butyl dicarbonate (0.749 g, 3.43 mmol) was added to a solutionof 3-methylamino-1-propanol (0.327 mL, 3.37 mmol) in dry DCM (12 mL).The reaction mixture was stirred at rt for 2 hrs, and then washed withbrine (1×). The aqueous phase was extracted with DCM (1×) and thecombined organic phases were dried (MgSO4), filtered and concentrated toafford the intermediate compound (640 mg, 100%) as a colourless oilwhich was used without further purification. NaH (60% in mineral oil,0.073 g, 1.82 mmol) was added to a solution of this intermediate (0.300g, 1.58 mmol) in dry THF (5 mL) at 0° C. The reaction mixture wasstirred for 5 min, then allowed to warm to rt, and stirred for 30 minbefore 6-bromo-2-chloroquinoline (0.384 g, 1.58 mmol) was added. Thereaction mixture was heated at reflux for 4 hrs, cooled, concentrated,diluted with water and saturated NaHCO₃(aq), and extracted with DCM(2×). The organic phase was dried (MgSO₄), filtered and concentrated.Unreacted 6-bromo-2-chloroquinoline (˜70 mg) was removed bycrystallizing it from hot ethanol. The filtrate was concentrated andthen purified by silica gel column chromatography using a gradient of 10to 12.5% EtOAc in PE to afford the title compound (348 mg, 56%) as acolourless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.88 (d, J=8.9 Hz, 1H), 7.85(br s, 1H), 7.68-7.65 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 4.47 (t, J=6.4Hz, 2H), 3.42 (br s, 2H), 2.89 (s, 3H), 2.10-1.98 (m, 2H), 1.43 (s, 9H).HRMS (ESI⁺): calcd for C_(1B)H₂₄ ⁷⁹BrN₂O₃(M+H)⁺, 395.0965; found395.0963.

Preparation of Compound 10,2-(3-((tert-butoxycarbonyl)(methyl)amino)propoxy) quinoline-6-carboxylicacid

nBuLi (2.2 M in hexanes, 0.13 mL, 0.29 mmol) was added dropwise to asolution of Compound 9 (0.105 g, 0.266 mmol) in dry THF (1 mL) at −78°C. The reaction mixture was stirred at this temp for 35 min before solidCO₂ was added. After stirring for 5 min, the reaction mixture wasallowed to warm to rt, quenched with water, and then concentrated toremove THF, diluted with water, washed with EtOAc (1×). The aqueousphase was acidified with 2 M HCl to pH 2-3 then extracted with DCM (2×).The DCM phase was dried (MgSO₄), filtered and concentrated to afford thetitle compound (68 mg, 71%) as a colourless oil that solidified overtime. ¹H NMR (500 MHz, CDCl₃) δ 8.54 (br s, 1H), 8.26 (dd, J=8.8, 2.1Hz, 1H), 8.07 (d, J=8.9 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 6.96 (d, J=8.9Hz, 1H), 4.53 (t, J=6.3 Hz, 2H), 3.44 (br s, 2H), 2.91 (s, 3H),2.11-2.04 (m, 2H), 1.44 (s, 9H). HRMS (ESI⁺): calcd for C₁₉H₂₅N₂O₅(M+H)⁺, 361.1758; found 361.1761.

Preparation of Compound 11, tert-butyl(3-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinolin-2-yl)oxy)propyl)(methyl)carbamate

This was prepared as for Example 1, substituting Compound 10 for6-quinolinecarboxylic acid. The crude material was purified by silicagel column chromatography using a gradient of 1 to 3% MeOH in DCM toafford the title compound in a yield of 71% as a white solid. ¹H NMR(500 MHz, CDCl₃) δ 8.30 (d, J=2.2 Hz, 1H), 8.14 (d, J=2.3 Hz, 1H), 8.09(d, J=9.0 Hz, 1H), 8.06 (dd, J=8.8, 2.1 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H),7.82 (s, 1H), 7.79 (s, 1H), 7.71 (dd, J=8.3, 1.9 Hz, 2H), 7.44 (d, J=2.2Hz, 1H), 7.37 (dd, J=8.4, 2.2 Hz, 1H), 7.25 (d, coupling obscured bysolvent peak, 1H), 6.98 (d, J=8.9 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 4.53(t, J=6.3 Hz, 2H), 4.34-4.27 (m, 4H), 3.49-3.42 (m, 2H), 2.91 (s, 3H),2.37 (s, 3H), 2.12-2.04 (m, 2H), 1.44 (s, 9H). HRMS (ESI⁺): calcd forC₃₅H₄₉N₅O₇ (M+H)⁺, 627.2813; found 627.2815.

Example 76,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(3-(methylamino)propoxy)quinoline-6-carboxamide

Trifluoroacetic acid (2.50 mL) was added to a solution of Compound 11(0.080 g, 0.13 mmol) in dry DCM (3 mL). The reaction mixture was stirredat rt for 40 min, diluted with DCM, washed with saturated NaHCO₃(aq)(2×)—note a precipitate formed that stuck to the glassware—this wasdissolved in MeOH, diluted with DCM, washed with water (1×), and thisaqueous phase was extracted with DCM (2×). The combined organic phaseswere dried (MgSO₄), filtered and concentrated. The crude solid wastriturated in ether and the solvent decanted (2×), to afford the titlecompound (46 mg, 68%) a white solid. ¹H NMR (500 MHz, DMSO) δ 10.07 (s,2H), 8.56 (d, J=2.1 Hz, 1H), 8.37 (d, J=8.8 Hz, 1H), 8.22 (dd, J=8.8,2.1 Hz, 1H), 7.88-7.84 (m, 2H), 7.58 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d,J=2.1 Hz, 1H), 7.51 (dd, J=8.4, 2.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H),7.10 (d, J=8.8 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 4.50 (t, J=6.5 Hz, 2H),4.33-4.28 (m, 4H), 2.68 (t, J=6.9 Hz, 2H), 2.32 (s, 3H), 2.23 (s, 3H),1.94 (p, J=6.7 Hz, 2H). HRMS (ESI⁺): calcd for C₃₀H₃₁N₄O₅ (M+H)⁺,527.2289; found 527.2288.

Preparation of Compound 12,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-vinylquinoline-6-carboxamide

A mixture of Example 39 (0.034 g, 0.075 mmol), dibenzyl (chloromethyl)phosphate (0.037 g, 0.11 mmol), tetrabutylammonium bromide (2.4 mg, 7.6μmol), and potassium carbonate (0.026 g, 0.19 mmol) in dry DMF (0.7 mL)was heated in a microwave at 100° C. for 30 min. The reaction mixturewas then cooled to rt, diluted with water, and the resulting precipitateisolated by filtration, washed with water and dried. The crude materialwas purified by silica gel column chromatography using a gradient of 50to 67% EtOAc in PE to afford the title compound (25 mg, 71%) as anoff-white solid. ¹H NMR (500 MHz, DMSO) δ 10.16 (s, 1H), 10.08 (s, 1H),8.62 (d, J=1.9 Hz, 1H), 8.51 (d, J=8.6 Hz, 1H), 8.27 (dd, J=8.8, 2.0 Hz,1H), 8.09 (d, J=8.8 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.88 (d, J=2.1 Hz,1H), 7.59 (dd, J=8.3, 2.2 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.51 (dd,J=8.5, 2.2 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.03 (dd, J=17.7, 10.9 Hz,1H), 6.98 (d, J=8.4 Hz, 1H), 6.49 (dd, J=17.7, 0.9 Hz, 1H), 5.76 (dd,J=11.0, 0.8 Hz, 1H), 4.34-4.28 (m, 4H), 2.25 (s, 3H). HRMS (ESI⁺): calcdfor C₂₈H₂₄N₃O₄ (M+H)⁺, 466.1761; found 466.1299.

Example 77,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-ethylquinoline-6-carboxamide

A suspension of Compound 12 (0.018 g, 0.039 mmol) in ethyl acetate (5mL) and methanol (3 mL) was heated gently in order to dissolve thesolid. The solution was degassed, to which 10% Pd/C (0.002 g, 0.04 mmol)was added and the reaction mixture was stirred under 1 atm hydrogen atrt for 3 hrs, filtered through celite with 1:1 MeOH:EtOAc, andconcentrated. The residue was purified by silica gel columnchromatography using a gradient of 25 to 33% EtOAc in DCM to afford thetitle compound (10 mg, 56%) as a white solid. ¹H NMR (500 MHz, DMSO) δ10.13 (s, 1H), 10.07 (s, 1H), 8.61 (d, J=1.9 Hz, 1H), 8.43 (d, J=8.4 Hz,1H), 8.25 (dd, J=8.8, 2.0 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.87 (d,J=2.1 Hz, 1H), 7.59 (dd, J=8.3, 2.2 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H),7.54 (d, J=2.1 Hz, 1H), 7.51 (dd, J=8.5, 2.2 Hz, 1H), 7.24 (d, J=8.5 Hz,1H), 6.98 (d, J=8.4 Hz, 1H), 4.34-4.28 (m, 4H), 2.99 (q, J=7.6 Hz, 2H),2.24 (s, 3H), 1.35 (t, J=7.6 Hz, 3H). HRMS (ESI⁺): calcd for C₂₈H₂₆N₃O₄(M+H)⁺, 468.1918; found 468.1886.

Preparation of Compound 13, methyl 2-formylquinoline-6-carboxylate

Methyl 2-methylquinoline-6-carboxylate (1.00 g, 4.97 mmol) was added toa suspension of selenium dioxide (0.689 g, 6.21 mmol) in dry 1,4-dioxane(7.1 mL). The reaction mixture was heated to 80° C. overnight, cooled,diluted with DCM, filtered through celite with DCM, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography using gradient of 20 to 40% EtOAc in PE to afford thetitle compound (737 mg, 69%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃)δ 10.25 (d, J=0.9 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H), 8.44 (d, J=8.5 Hz,1H), 8.40 (dd, J=8.8, 1.9 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.09 (d,J=8.5 Hz, 1H), 4.03 (s, 3H). HRMS (ESI⁺): calcd for C₁₂H₁₀NO₃ (M+H)⁺,216.0655; found 216.0658.

Preparation of Compound 14, methyl2-(((tert-butoxycarbonyl)(methyl)amino)methyl)quinoline-6-carboxylate

Methylamine (2 M in THF, 2.79 mL, 5.58 mmol) was added to a solution ofCompound 13 (0.400 g, 1.86 mmol) in dry DCM (15 mL). The reactionmixture was sealed and stirred at rt for 4 hrs. Na(OAc)₃BH (0.591 g,2.79 mmol) was added and the reaction mixture was stirred for 4 hrs,after which time more methylamine solution (2 M in THF, 0.93 mL, 1.86mmol) was added and the reaction mixture was stirred overnight at rt,diluted with DCM, washed with saturated NaHCO₃(aq). The aqueous phasewas extracted with DCM (1×). The combined organic phases were dried(MgSO₄), filtered and concentrated to provide the secondary amineintermediate which as used without any further purification. Thisintermediate (0.483 g, 2.10 mmol) was dissolved in dry DCM (10 mL), towhich was added di-tert-butyl dicarbonate (0.504 g, 2.31 mmol) and thereaction mixture was stirred at rt for 3 hrs, diluted with DCM, washedwith brine (1×). The aqueous phase was extracted with DCM (1×). Thecombined organic phases were dried (MgSO₄), filtered and concentrated.The residue was purified by silica gel column chromatography using agradient of 12.5 to 20% EtOAc in PE to afford the title compound (478mg, 69%) as a pale yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 8.58 (br s,1H), 8.29 (br d, J=8.7 Hz, 1H), 8.24 (br s, 1H), 8.07 (d, J=8.8 Hz, 1H),7.43 (br dd, J=27.5, 8.2 Hz, 1H), 4.74 (ap d, 2H), 2.95 (ap d, 3H), 1.48(ap d, 9H). Note that this NMR shows the presence of amide bond rotamersin ˜1:1 ratio. HRMS (ESI⁺): calcd for C₁₈H₂₃N₂O₄ (M+H)⁺, 331.1652; found331.1650.

Preparation of Compound 15,2-(((tert-butoxycarbonyl)(methyl)amino)methyl)quinoline-6-carboxylicacid

NaOH(aq) (1.988 M, 3.09 mL, 6.14 mmol) was added to a solution ofCompound 14 (0.406 g, 1.23 mmol) in THF (6 mL). MeOH (2.5 mL) was addedand the reaction mixture was stirred overnight at rt, concentrated toremove organic solvents, diluted with water, washed with EtOAc (1×). Theaqueous phase was acidified with 2 M HCl to pH 3, and the resultingsolid isolated by filtration, washed with water and dried to afford thetitle compound (344 mg, 88%) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ8.66 (ap d, 1H), 8.38-8.32 (m, 1H), 8.32-8.23 (m, 1H), 8.13 (d, J=8.9Hz, 1H), 7.52-7.40 (m, 1H), 4.77 (ap d, 2H), 2.97 (ap d, 3H), 1.48 (apd, 9H). Note that this spectrum shows the presence of amide bondrotamers in ˜1:1 ratio. HRMS (ESI⁺): calcd for C₁₇H₂₁N₂O₄ (M+H)⁺,317.1496; found 317.1499.

Preparation of Compound 16, tert-butyl((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinolin-2-yl)methyl)(methyl)carbamate

The title compound was prepared as for Example 1 using Compound 15 inplace of 6-quinolinecarboxylic acid. ¹H NMR (500 MHz, CDCl₃) δ 8.40 (brs, 1H), 8.30-8.24 (m, 1H), 8.19-8.14 (m, 2H), 7.96 (br s, 1H), 7.92-7.86(m, 2H), 7.72 (br d, J=8.1 Hz, 1H), 7.58-7.52 (m, 1H), 7.52-7.41 (m,3H), 7.26 (d, J=8.0 Hz, 2H), 4.76 (ap d, 2H), 2.97 (ap d, 3H), 1.48 (apd, 9H). Note that this spectrum shows a mixture of amide bond rotamersin ˜1:1 ratio. Only the actual coupling constants are listed, not theapparent ones. HRMS (ESI⁺): calcd for C₃₃H₃₅N₄O₆ (M+H)⁺, 583.2554; found583.2546.

Example 78,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((N-methylpropionamido)methyl)quinoline-6-carboxamide

TFA (1.0 mL) was added to a solution of Compound 16 (0.056 g, 0.096mmol) in dry DCM (1.5 mL). The reaction mixture was stirred at rt for 45min, diluted with DCM, washed with saturated NaHCO₃(aq) (1×) whichcaused a sticky solid to form. This was dissolved using a mixture of DCMand MeOH, and this org phase was washed with saturated NaHCO₃(aq) (1×).This aqueous phase was extracted with DCM (1×), then diluted with waterand brine, and then extracted with CHCl₃ (1×). The combined organicphases were washed with brine (1×), dried (MgSO₄), filtered andconcentrated to afford the crude intermediate (44 mg) as an off-whitesolid, Propionyl chloride (3.0 μL, 0.034 mmol) was added to a solutionof the intermediate (0.015 g, 0.031 mmol) and N,N-diisopropylethylamine(8.1 μL, 0.047 mmol) in dry DCM (0.5 mL). The reaction mixture wasstirred at rt for 3.5 hrs, concentrated, and the resulting white solidtriturated in water, and the solid isolated by filtration, washed withwater and dried to afford the title compound (12.5 mg, 70% over 2 steps)as a white solid. ¹H NMR (500 MHz, DMSO) δ 10.16 (s, 1H), 10.07 (s, 1H),8.65 (ap dd, J=2.1 Hz, 1H), 8.52 (ap dd, J=8.5 Hz, 1H), 8.31-8.25 (m,1H), 8.08 (ap dd, J=8.8 Hz, 2H), 7.88 (s, 1H), 7.59 (dd, J=8.3, 2.2 Hz,1H), 7.54 (d, J=2.2 Hz, 1H), 7.51 (dd, J=8.5, 2.2 Hz, 1H), 7.44 (d,J=8.5 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.85 (apd, 2H), 4.36-4.25 (m, 4H), 3.02 (ap d, 3H), 2.43 (ap dq, J=7.3 Hz, 2H),2.25 (s, 3H), 1.02 (ap dt, J=7.3 Hz, 5H). Note that this spectrum showsa mixture of amide bond rotamers in ˜1.8:1 ratio. Only the actualcoupling constants are listed, not the apparent ones. HRMS (ESI⁺): calcdfor C₃₁H₃₁N₄O₅ (M+H)⁺, 539.2289; found 539.2283.

Preparation of Compound 17,² ethyl 2-chloroquinoline-6-carboxylate

3-Chloroperbenzoic acid (75%, 1.675 g, 7.280 mmol) was added to asolution of ethyl quinoline-6-carboxylate (1.127 g, 5.601 mmol) in dryDCM (16 mL) at 0° C. The reaction mixture was then allowed to warm tort, and stirred overnight. The reaction mixture was washed with 10%aqueous sodium sulfite (1×), saturated NaHCO₃(aq) (1×), brine (1×),dried (MgSO₄), filtered and concentrated to give the N-oxideintermediate (1.22 g, 100%) as a pale brown solid. The N-oxideintermediate was dissolved in dry DCM (14 mL), and to this was addedphosphorus oxychloride (6.94 mL, 74.5 mmol) and the reaction mixture washeated to 50° C. overnight, cooled to rt, concentrated, diluted withDCM, washed with saturated NaHCO₃(aq) (1×). Due to the presence of anemulsion, the organic phase (and majority of the mixed emulsion) wasconcentrated, diluted with EtOAc, washed with saturated NaHCO₃(aq) (2×).The aqueous phase was extracted with EtOAc (1×), and the combinedorganic phases washed with brine (1×), dried (MgSO₄), filtered andconcentrated. The residue was purified by silica gel columnchromatography first using a gradient of 6.7 to 25% EtOAc in PE, andthis still impure material was re-purified by silica gel columnchromatography using a gradient of 0 to 1.5% EtOAc in toluene to affordthe title compound (270 mg, 20%) as a white solid. ¹H NMR (500 MHz,CDCl₃) δ 8.58 (d, J=1.8 Hz, 1H), 8.34 (dd, J=8.8, 1.9 Hz, 1H), 8.21 (d,J=8.6 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 4.46 (q,J=7.1 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H). HRMS (ESI⁺): calcd for C₁₂H₁₁³⁵ClNO₂ (M+H)⁺, 236.0473; found 236.0473.

Preparation of Compound 18, 2-chloroquinoline-6-carboxylic acid

A suspension of Compound 17 (0.100 g, 0.424 mmol) in HCl (32%, 2 mL) washeated to 95° C. for 75 min, cooled to rt and concentrated to dryness.The residue was purified by silica gel column chromatography using 1:1PE:EtOAc+0.5% acetic acid to afford the title compound (28 mg, 32%) as awhite solid. ¹H NMR (500 MHz, DMSO) δ 13.37 (br s, 1H), 8.73 (d, J=1.9Hz, 1H), 8.66 (d, J=8.6 Hz, 1H), 8.26 (dd, J=8.8, 1.9 Hz, 1H), 8.03 (d,J=8.8 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H). HRMS (ESI⁺): calcd for C₁₀H₇³⁵ClNO₂ (M+H)⁺, 208.0160; found 208.0162.

Preparation of Compound 19,2-chloro-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide

The title compound was prepared as for Example 1 using Compound 18 inplace of 6-quinolinecarboxylic acid. ¹H NMR (500 MHz, DMSO) δ 10.22 (s,1H), 10.08 (s, 1H), 8.72 (d, J=1.9 Hz, 1H), 8.63 (d, J=8.4 Hz, 1H), 8.34(dd, J=8.8, 2.0 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H),7.71 (d, J=8.6 Hz, 1H), 7.59 (dd, J=8.3, 2.2 Hz, 1H), 7.54 (d, J=2.1 Hz,1H), 7.51 (dd, J=8.5, 2.2 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.98 (d,J=8.4 Hz, 1H), 4.33-4.28 (m, 4H), 2.24 (s, 3H). HRMS (ESI⁺): calcd forC₂₆H₂₁ ³⁵ClN₃O₄(M+H)⁺, 474.1215; found 474.1181.

Example 79,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(methylamino)quinoline-6-carboxamide

A suspension of Compound 19 (0.025 g, 0.053 mmol) in methylamine (33% inEtOH, 0.75 mL) was heated in the microwave at 100° C. for 75 min,diluted with water producing a colloidal suspension that was notfilterable. This mixture was concentrated nearly to dryness, thentriturated in water. The resulting precipitate was isolated byfiltration, washed with water and dried to afford the title compound (17mg, 68%) as an off-white solid. ¹H NMR (500 MHz, DMSO) δ 10.05 (s, 1H),9.87 (s, 1H), 8.31 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.95 (d, J=8.8 Hz,1H), 7.84 (s, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.53 (s, 1H), 7.51 (d, J=8.5Hz, 2H), 7.31 (d, J=4.5 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.98 (d, J=8.4Hz, 1H), 6.82 (d, J=8.9 Hz, 1H), 4.38-4.25 (m, 4H), 2.93 (d, J=4.6 Hz,3H), 2.22 (s, 3H). HRMS (ESI⁺): calcd for C₂₇H₂₅N₄O₄ (M+H)⁺, 469.1870;found 469.1875.

Example 80—Preparation ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide

A suspension of Example 39 (0.097 g, 0.22 mmol) and Pd/C (10%, 0.025 g)in MeOH (8 mL), Ethyl acetate (6 mL), and 10 drops glacial acetic acidwas stirred under 1 atm hydrogen at 40° C. overnight, filtered throughcelite with EtOAc, and concentrated. The residue was purified by silicagel column chromatography using a gradient of 10 to 22% EtOAC in DCM toafford the title compound (72 mg, 74%) as a white solid. ¹H NMR (500MHz, DMSO) δ 10.01 (s, 1H), 9.34 (s, 1H), 7.76 (d, J=2.2 Hz, 1H),7.57-7.52 (m, 4H), 7.50 (dd, J=8.5, 2.2 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H),6.97 (d, J=8.4 Hz, 1H), 6.46 (d, J=9.0 Hz, 1H), 6.34 (br s, 1H),4.34-4.27 (m, 4H), 3.27-3.20 (m, 2H), 2.71 (t, J=6.2 Hz, 2H), 2.16 (s,3H), 1.85-1.76 (m, 2H).

HRMS (ESI⁺): calcd for C₂₆H₂₆N₃O₄ (M+H)⁺, 444.1718; found 444.1812.

Example 81—Preparation ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-propionamidoethoxy)quinoline-6-carboxamide

Propionyl chloride (2.5 μL, 0.029 mmol) was added to a solution ofExample 89 (0.013 g, 0.026 mmol) in dry DCM (0.75 mL) and DMF (0.15 mL).The reaction mixture was stirred at rt for 2.5 hrs, concentrated toremove DCM, then diluted with water, extracted with DCM (3×), dried overMgSO₄, filtered and concentrated. Added heptane and concentrated (2×) toremove residual DMF. The crude material was purified by silica gelcolumn chromatography using a gradient of 2 to 3.5% MeOH in DCM toafford the title compound (10 mg, 71%) as a white solid. ¹H NMR (500MHz, DMSO) δ 10.07 (s, 1H), 10.07 (s, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.39(d, J=8.8 Hz, 1H), 8.23 (dd, J=8.7, 2.1 Hz, 1H), 8.04 (br t, J=5.5 Hz,1H), 7.88-7.84 (m, 2H), 7.58 (dd, J=8.4, 2.2 Hz, 1H), 7.54 (d, J=2.1 Hz,1H), 7.51 (dd, J=8.5, 2.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.11 (d,J=8.8 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.47 (t, J=5.7 Hz, 2H), 4.34-4.27(m, 4H), 3.51 (q, J=5.7 Hz, 2H), 2.23 (s, 3H), 2.10 (q, J=7.6 Hz, 2H),0.99 (t, J=7.6 Hz, 3H). HRMS (ESI⁺): calcd for C₃₁H₃₁N₄O₆ (M+H)⁺,555.2238; found 555.2228.

Preparation of Compound 20,³ 6-bromo-3,4-dihydronaphthalen-1(2H)-one

A solution of 6-amino-1,2,3,4-tetrahydronaphthalen-1-one (0.500 g, 3.10mmol) in 8 mL 25% HBr(aq) and 1 mL 50% HBr(aq) was cooled to 0° C.before a solution of sodium nitrite (0.263 g, 3.82 mmol) in water (1.25mL) was added dropwise. This reaction mixture was then added dropwise toa cooled solution of copper(I) bromide (0.458 g, 3.19 mmol) in 50%HBr(aq) (2.38 mL). The reaction mixture was stirred at 0° C. for 1 h,then warmed to rt, diluted with a bit of water, extracted with 4:1Et₂O:EtOAc (3×). The combined organic phases were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by silica gelcolumn chromatography using 12:1 PE:EtOAc to afford the title compound(444 mg, 64%) as a pale orange oil. ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d,J=9.0 Hz, 1H), 7.46-7.42 (m, 2H), 2.94 (t, J=6.1 Hz, 2H), 2.68-2.61 (m,2H), 2.14 (m, 2H). HRMS (ESI⁺): calcd for C₁₀H₁₀ ⁷⁹BrO (M+H)⁺, 224.9910;found 224.9910.

Preparation of Compound 21, (E)-6-bromo-3,4-dihydronaphthalen-1(2H)-oneoxime

To a suspension of hydroxylamine hydrochloride (0.204 g, 2.93 mmol) indry EtOH (2.5 mL) was added potassium acetate (0.288 g, 2.93 mmol),followed by a solution of Compound 20 (0.440 g, 1.96 mmol) in dry EtOH(2.5 mL). The reaction mixture was heated at reflux for 75 min, cooled,and concentrated. To the residue was added water and the resultingprecipitate was isolated by filtration, washed with water and dried toafford the title compound (429 mg, 91%) as a pale yellow solid. ¹H NMR(500 MHz, CDCl₃) δ 7.77 (d, J=8.9 Hz, 1H), 7.51 (br s, 1H), 7.34-7.30(m, 2H), 2.79 (t, J=6.7 Hz, 2H), 2.76-2.71 (m, 2H), 1.92-1.82 (m, 2H).HRMS (ESI⁺): calcd for C₁₀H₁₁ ⁷⁹BrNO (M+H)⁺, 240.0018; found 240-0018.

Preparation of Compound 22, tert-butyl7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate

Diisobutylaluminum hydride (1 M in hexanes) (9.86 mL, 9.86 mmol) wasadded dropwise over 10 min to a solution of Compound 21 (0.263 g, 1.10mmol) in dry DCM (10 mL) at 0° C. After stirring for a few minutes, thereaction mixture was warmed to rt and stirred for 3 days, cooled to 0°C., then added sodium fluoride (1.84 g, 43.8 mmol) followed by water(0.75 mL) dropwise. Stirred at 0° C. for 1 hr, then filtered throughcelite with EtOAc, and the filtrate concentrated to afford theintermediate 7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine as a paleyellow oil. This material was combined with 45 mg of crude material froma separate reaction, dissolved in dry DCM (4 mL) to which di-tert-butyldicarbonate (0.411 g, 1.88 mmol) was added and the reaction mixture wasthen stirred at rt overnight.

4-Dimethylaminopyridine (0.015 g, 0.13 mmol) was then added and reactionmixture was heated at reflux for 4 hrs, cooled, diluted with DCM, washedwith 0.5 M HCl (1×), water (1×), dried (MgSO₄), filtered andconcentrated. The crude residue was purified by silica gel columnchromatography using a gradient of 5% to 8% EtOAc in PE to afford thetitle compound (258 mg, 63%) as a colourless oil. ¹H NMR (500 MHz,CDCl₃) δ 7.36 (d, J=2.3 Hz, 1H), 7.33 (dd, J=8.3, 2.3 Hz, 1H), 7.08 (d,J=8.3 Hz, 1H), 2.95-2.86 (m, 2H), 2.86-2.75 (m, 2H), 2.05-1.95 (m, 2H),1.93-1.73 (m, 2H), 1.41 (s, 9H). LRMS (ESI⁺): 270.01, 272.01 (1:1,dp-^(t)Bu), and 226.02, 228.02 (1:1, dp-Boc)

Preparation of Compound 23, tert-butyl7-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate

nBuLi (1.84 M in hexanes, 0.313 mL, 0.577 mmol) was added dropwise to asolution of Compound 22 (0.171 g, 0.524 mmol) in dry THF (2.5 mL) at−78° C. The reaction mixture was stirred at this temperature for 35 min,and then solid CO₂ was added. The reaction mixture was stirred at −78°C. for a few minutes, then allowed to warm to rt, stirred for 20 min,and then quenched with water and concentrated to dryness to afford theintermediate lithium1-(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-carboxylateas a pale brown solid. A portion of this intermediate (0.060 g, 0.20mmol) and N,N-diisopropylethylamine (0.088 mL, 0.50 mmol) was dissolvedin dry DMF (1.5 mL). To this was added2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU, 0.104 g, 0.272 mmol) followed by Compound 2(0.043 g, 0.151 mmol) and the reaction mixture was stirred at rtovernight, diluted with water and the resulting precipitate isolated byfiltration, washed with water and dried. The crude material was purifiedby silica gel column chromatography using a gradient of 10 to 14% EtOAcin DCM to afford the title compound (22 mg, 26%) as a pale brownamorphous solid. ¹H NMR (500 MHz, CDCl₃) δ 8.09 (br s, 1H), 7.77 (br s,1H), 7.73 (br s, 1H), 7.71-7.66 (m, 1H), 7.65 (dd, J=8.3, 2.2 Hz, 1H),7.43 (d, J=2.2 Hz, 1H), 7.37 (dd, J=8.5, 2.2 Hz, 1H), 7.23 (d, J=8.5 Hz,1H), 6.94 (d, J=8.3 Hz, 1H), 4.35-4.26 (m, 4H), 2.85-2.80 (m, 2H), 2.33(br s, 3H), 1.89-1.75 (m, 4H), 1.52 (br s, 2H), 1.39 (br s, 9H). HRMS(ESI⁺): calcd for C₃₂H₃₆N₃O₆ (M+H)⁺, 558.2599; found 558.2582.

Example 82,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-carboxamide

Trifluoroacetic acid (0.50 mL, 6.5 mmol) was added to a solution ofCompound 23 (0.016 g, 0.029 mmol) in dry DCM (0.75 mL). The reactionmixture was stirred at rt for 1 h, and then concentrated. A small amountof MeOH was added to dissolve the residue, followed by a small amount ofwater, and finally saturated NaHCO₃(aq). The resulting precipitate wasisolated by filtration, washed with water and dried. The residue waspurified by silica gel column chromatography using a gradient of 14 to20% EtOAc in DCM to afford the title compound (7 mg, 53%) as anoff-white solid. ¹H NMR (500 MHz, DMSO) δ 10.03 (s, 1H), 9.53 (s, 1H),7.78 (d, J=2.2 Hz, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.62 (dd, J=8.3, 2.2 Hz,1H), 7.54 (dd, J=8.3, 2.3 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.50 (dd,J=8.4, 2.2 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.84(d, J=8.2 Hz, 1H), 4.33-4.27 (m, 4H), 3.07-3.02 (m, 2H), 2.79-2.72 (m,2H), 2.17 (s, 3H), 1.76-1.70 (m, 2H), 1.69-1.63 (m, 2H). HRMS (ESI⁺):calcd for C₂₇H₂₈N₃O₄ (M+H)⁺, 458.2074; found 458.2081.

Preparation of Compound 24, ethyl2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)quinoline-6-carboxylate

N-Boc-ethylenediamine (0.082 mL, 0.52 mmol) was added to a solution ofCompound 17 (0.081 g, 0.34 mmol) and N,N-diisopropylethylamine (0.120mL, 0.687 mmol) in dry THF (1.5 mL). The reaction mixture was heated atreflux for 24 hrs. The material was then transferred to a microwave vialand heated at 100° C. for 2 hrs, 110° C. for 8 hrs, and then at 120° C.for 3 hrs. An additional amount of N-Boc-ethylenediamine (0.054 mL, 0.34mmol) was added and the reaction mixture was heated in the microwave at120° C. for 2 hrs, and then stood at rt for 5 days, concentrated,diluted with EtOAc, washed with water. The aqueous phase was acidifiedwith a few drops of 2 M HCl, then used to wash the organic phase. Theresulting aqueous phase was again acidified and used to wash the organicphase. The resulting aqueous phase was adjusted to pH 3-4 with 1 M NaOH,then used to wash the organic phase. The organic phase was washed withbrine (1×), dried (MgSO₄), filtered and concentrated. The crude residuewas purified by silica gel column chromatography using a gradient of 28%to 50% EtOAc in PE to afford the title compound (39 mg, 32%) as anoff-white amorphous solid. HRMS (ESI⁺): calcd for C₁₉H₂₆N₃O₄ (M+H)⁺,360.1918; found 360.1924.

Preparation of Compound 25,2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)quinoline-6-carboxylicacid

NaOH (0.95 M, 0.343 mL, 0.33 mmol) was added to a solution of Compound24 (0.039 g, 0.11 mmol) in THF (1 mL), followed by MeOH (0.25 mL). Thereaction mixture was stirred at rt overnight, and then more NaOH (0.95M, 0.343 mL, 0.33 mmol) was added, and the reaction mixture was stirredat rt for 24 hrs. An additional aliquot of NaOH (0.95 M, 0.200 mL, 0.19mmol) was added and the reaction mixture was stirred at rt for for 4hrs, concentrated to remove organic solvents, diluted with water, andwashed with EtOAc (1×). The aqueous phase was acidified with 2 M HCl topH 4 (precipitate appeared), and the mixture was extracted with DCM(1×), CHCl₃(1×), and then EtOAC(2×). The combined organic phases werewashed with brine (1×), dried (MgSO₄), filtered and concentrated toafford the title compound (23 mg, 64%) as a colourless glass. HRMS(ESI⁺): calcd for C₁₇H₂₂N₃O₄ (M+H)⁺, 332.1605; found 332.1602.

Preparation of Compound 26, tert-butyl(2-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinolin-2-yl)amino)ethyl)carbamate

This was prepared as for Example 1, substituting Compound 8 for6-quinolinecarboxylic acid. The crude material was purified by silicagel column chromatography using a gradient of 1 to 5% MeOH in DCM toafford the title compound in a yield of 26% as an off-white solid. HRMS(ESI⁺): calcd for C₃₃H₃₆N₅O₆ (M+H)⁺, 598.2660; found 598.2660.

Preparation of Compound 27,2-((2-aminoethyl)amino)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide

TFA (0.5 mL) was added to a solution of Compound 26 (0.010 g, 0.018mmol) in dry DCM (0.5 mL) and the reaction mixture was stirred at rt for80 min, concentrated, diluted with DCM, washed with saturated NaHCO₃(aq)(1×). The aqueous phase was extracted with DCM (1×), EtOAc (1×). Thecombined organic phases were washed with brine (1×). A sticky residue onthe walls of the separating funnel was dissolved in MeOH and added tothe org phases before drying over MgSO₄, filtering and concentrating toafford the title compound (7.5 mg, 86%) as an off-white solid. HRMS(ESI⁺): calcd for C₂₈H₂₈N₅O₄ (M+H)⁺, 498.2136; found 498.2124.

Example 83,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((2-propionamidoethyl)amino)quinoline-6-carboxamide

Propionyl chloride (1.4 μL, 0.017 mmol) was added to a solution ofCompound 27 (0.0075 g, 0.015 mmol) and N,N-diisopropylethylamine (4.0μL, 0.023 mmol) in dry DCM (0.5 mL). The reaction mixture was stirred atrt for 4.5 hrs, concentrated and the residue triturated in water. Theresulting precipitate was isolated by filtration, washed with water anddried to afford the title compound (3.5 mg, 42%) as a white solid. ¹HNMR (500 MHz, DMSO) δ 10.05 (s, 1H), 9.88 (s, 1H), 8.32 (s, 1H), 8.06(d, J=7.5 Hz, 1H), 8.00-7.91 (m, 2H), 7.84 (d, J=2.2 Hz, 1H), 7.60-7.54(m, 2H), 7.53 (d, J=2.2 Hz, 1H), 7.51 (dd, J=8.3, 2.2 Hz, 1H), 7.42-7.37(m, 1H), 7.22 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.83 (br d,J=8.8 Hz, 1H), 4.34-4.28 (m, 4H), 3.52-3.46 (m, 2H), 3.34-3.28 (m, 2H),2.22 (s, 3H), 2.09 (q, J=7.6 Hz, 2H), 0.99 (t, J=7.6 Hz, 3H). HRMS(ESI⁺): calcd for C₃₁H₃₂N₅O₅ (M+H)⁺, 554.2398; found 554.2386.

Preparation of Compound 28,⁴ methyl indoline-5-carboxylate

A mixture of methyl indole-5-carboxylate (0.500 g, 2.85 mmol) in AcOH (5mL) was warmed to dissolve all solid. The solution was then cooled in anice bath, and sodium cyanoborohydride (0.538 g, 8.56 mmol) was addedportionwise over 10 min. Note that upon addition, the solution froze,thus was warmed a bit in order to achieve stirring, and occasionallycooled during the addition. After the addition was complete, thereaction mixture was allowed to warm to rt, and stirred for 1 hr. Water(1.5 mL) was added, and the reaction mixture was concentrated to leave aviscous oil. EtOAc was added, washed with saturated NaHCO₃(aq) (2×). Theaqueous phase was extracted with EtOAc (2×). The combined organic phaseswere washed with brine (1×), dried (MgSO₄), filtered and concentrated.The crude material was purified by silica gel column chromatographyusing 1:1 PE to afford the title compound (344 mg, 68%) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ 7.77-7.74 (m, 2H), 6.55 (d, J=8.6 Hz,1H), 4.11 (br s, 1H), 3.84 (s, 3H), 3.65 (t, J=8.5 Hz, 2H), 3.06 (t,J=8.5 Hz, 2H). HRMS (ESI⁺): calcd for C₁₀H₁₂NO₂ (M+H)⁺, 178.0863; found178.0865.

Preparation of Compound 29, 1-tert-butyl 5-methylindoline-1,5-dicarboxylate

Di-tert-butyl dicarbonate (0.489 g, 2.24 mmol), followed bytriethylamine (0.315 mL, 2.24 mmol) was added to a solution of Compound28 (0.328 g, 1.85 mmol) in dry DCM (5.8 mL) and the reaction mixture wasstirred at rt for 26 hrs, concentrated. The residue was dissolved inEtOAc and washed with water (1×), brine (1×), dried (MgSO₄), filteredand concentrated. The crude material was recrystallized from hot EtOH toafford the title compound (373 mg, 73%) as a white solid. ¹H NMR (500MHz, CDCl₃) δ 7.88 (d, J=7.6 Hz, 1H), 7.82-7.79 (m, 1H), 4.02 (t, J=8.7Hz, 2H), 3.88 (s, 3H), 3.14-3.09 (m, 2H), 1.57 (br s, 9H). Note thatthere also appears to be 2 extremely broad and weak singlets centred at7.85 and 7.50 ppm which may be the missing aromatic CH. LRMS (ESI⁺):178.09 (loss of Boc) and very weak 278.15

Preparation of Compound 30, 1-(tert-butoxycarbonyl)indoline-5-carboxylicacid

A solution of LiOH.H₂O (0.086 g, 2.05 mmol) in water (5 mL) was added toa solution of Compound 29 (0.284 g, 1.02 mmol) in THF (5 mL) and thereaction mixture was stirred at rt for 3 days after which point a smallamount of MeOH was added to clear the cloudiness of the reactionmixture. NaOH (1.98 M, 1.03 mL, 2.05 mmol) was then added and thereaction mixture stirred at rt for 23.5 hrs, concentrated to removeorganic solvents, then acidified with 2 M HCl to pH 3 and the resultingsolid isolated by filtration, washed with water and dried to afford thetitle compound (257 mg, 95%) as a white solid. ¹H NMR (500 MHz, DMSO) δ12.56 (br s, 1H), 7.77 (dd, J=8.2, 1.8 Hz, 1H), 7.73 (d, J=1.3 Hz, 1H),7.70 (v br s, 1H), 3.95 (t, J=8.8 Hz, 2H), 3.09 (t, J=8.7 Hz, 2H), 1.51(s, 9H). LRMS (ESI⁺): 164.07 (loss of Boc).

Example 84,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)indoline-5-carboxamide

Trifluoroacetic acid (1.56 mL, 20.2 mmol) was added to a suspension ofExample 30 (0.074 g, 0.14 mmol) in dry DCM (2 mL) and the reactionmixture was stirred at rt for 1.5 hrs, concentrated, added DCM andconcentrated again. Water, followed by saturated NaHCO₃(aq) was added tothe residue and mixture was then triturated and sonicated, and theresulting solid isolated by filtration, washed with water and dried. Thecrude material was purified by silica gel column chromatography using 2%MeOH in DCM to afford the title compound (47 mg, 78%) as a white solid.¹H NMR (500 MHz, DMSO) δ 10.02 (s, 1H), 9.40 (s, 1H), 7.78 (d, J=2.2 Hz,1H), 7.68 (s, 1H), 7.64 (dd, J=8.2, 1.9 Hz, 1H), 7.56-7.52 (m, 2H), 7.50(dd, J=8.4, 2.2 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H),6.50 (d, J=8.1 Hz, 1H), 6.12 (br s, 1H), 4.33-4.28 (m, 4H), 3.52 (td,J=8.7, 1.5 Hz, 2H), 2.98 (t, J=8.6 Hz, 2H), 2.17 (s, 3H). HRMS (ESI⁺):calcd for C₂₅H₂₄N₃O₄ (M+H)⁺, 430.1761; found 430.1747.

Example 85—Preparation of tert-butyl((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)-1,2,3,4-tetrahydroquinolin-2-yl)methyl)(methyl)carbamate

All mixture of Compound 16 (0.177 g, 0.304 mmol) and Pd/C (10%, 0.035 g)in EtOAc (6 mL) and EtOH (6 mL) was stirred under 1 atm H₂ at 40° C. for22 hrs after which time additional Pd/C (10%, 0.035 mg) was added andthe reaction mixture stirred under 1 atm H2 at 45° C. for 18 hrs, thenat 50° C. for 8 hrs, filtered through celite with EtOAc, concentratedand the residue was purified by silica gel column chromatography using3:1 DCM:EtOAc to afford the title compound (151 mg, 85%) as a whiteamorphous solid. ¹H NMR (500 MHz, CDCl₃) δ 8.07 (d, J=2.2 Hz, 1H), 7.79(s, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.57 (s, 1H), 7.54 (br s, 1H), 7.50 (brd, J=8.2 Hz, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.36 (dd, J=8.4, 2.2 Hz, 1H),7.20 (d, J=8.3 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.48 (d, J=8.3 Hz, 1H),4.33-4.28 (m, 4H), 3.67-3.60 (m, 1H), 3.39 (d, J=7.4 Hz, 1H), 3.30 (v brs, 1H), 2.95 (s, 3H), 2.86-2.83 (m, 2H), 2.31 (s, 3H), 1.98-1.90 (br s,1H), 1.74-1.65 (m, 1H), 1.48 (s, 9H). HRMS (ESI⁺): calcd for C₃₃H₃₉N₄O₆(M+H)⁺, 587.2864; found 587.2897.

Example 86—Preparation ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((methylamino)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide

TFA (1.5 mL) was added to a solution of Example 85 (0.144 g, 0.245 mmol)in dry DCM (2 mL) and the reaction mixture was stirred at rt for 1 hr,concentrated, added DCM and concentrated again. The residue wasdissolved in DCM, and washed with saturated NaHCO₃(aq) causing a solidto form which stuck to the walls of the separating funnel. The aqueousphase was extracted with DCM (1×). The solid stuck to the flask wasdissolved with a small amount of MeOH, then DCM was added and thismixture washed with water (1×). This aqueous phase was extracted withDCM (1×) and the combined organic phases were dried (Na₂SO₄), filteredand concentrated. The crude material was suspended in a few mLs of MeOHand then diluted with water. The resulting solid was isolated byfiltration, washed with water and dried to afford the title compound (92mg, 77%) as a white solid. ¹H NMR (500 MHz, DMSO) δ 10.01 (s, 1H), 9.34(s, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.58-7.52 (m, 4H), 7.50 (dd, J=8.4, 2.2Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 6.56 (d, J=8.4Hz, 1H), 6.17 (s, 1H), 4.33-4.28 (m, 4H), 3.39-3.33 (m, 1H), 2.79-2.65(m, 2H), 2.57 (dd, J=11.6, 5.2 Hz, 1H), 2.54-2.47 (m, 1H), 2.32 (s, 3H),2.16 (s, 3H), 1.93-1.86 (m, 1H), 1.57-1.48 (m, 1H). HRMS (ESI⁺): calcdfor C₂₈H₃₁N₄O₄ (M+H)⁺, 487.2340; found 487.2327.

Example 87—Preparation ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((dimethylamino)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of MeI (50 uL in 2 mL CH₃CN) was made, and 113.2 uL of thissolution was added slowly to a suspension of Example 86 (0.020 g, 0.041mmol) and potassium carbonate (8.5 mg, 0.062 mmol) in dry acetonitrile(1.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 min,then allowed to warm to rt and stirred for 70 min, at which point solidadhering to the upper walls of the flask was rinsed into the reactionmixture with DMF (0.5 mL) and the reaction was stirred at rt for afurther 2.5 hrs. An additional amount of MeI solution (0.020 mmol) wasadded and the reaction mixture stirred for a further 40 min, dilutedwith water, extracted with DCM (3×). The organic phase was dried(MgSO₄), filtered and concentrated. Heptane was added and the mixtureconcentrated (2×) to remove residual DMF. The crude material waspurified by silica gel column chromatography using a gradient of 2% to4% 2 M NH₃-MeOH in DCM, to afford the title compound (14 mg, 68%) as awhite solid. ¹H NMR (500 MHz, DMSO) δ 10.01 (s, 1H), 9.35 (s, 1H), 7.77(d, J=2.2 Hz, 1H), 7.59-7.52 (m, 4H), 7.50 (dd, J=8.5, 2.2 Hz, 1H), 7.17(d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H), 5.99(s, 1H), 4.33-4.28 (m, 4H), 3.47-3.38 (m, 1H), 2.82-2.65 (m, 2H), 2.33(dd, J=11.8, 8.5 Hz, 1H), 2.26-2.22 (m, 1H), 2.21 (s, 6H), 2.16 (s, 3H),1.92-1.85 (m, 1H), 1.53-1.43 (m, 1H). HRMS (ESI⁺): calcd for C₂₉H₃₃N₄O₄(M+H)⁺, 501.2496; found 501.2496.

Preparation of Compound 31, tert-butyl6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

This was prepared as for Example 1, substitutingN-Boc-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid for6-quinolinecarboxylic acid. The crude material was purified by silicagel column chromatography using a gradient of 44 to 67% EtOAc in PE,then 3-5% MeOH in DCM to afford the title compound in a yield of 95% asa white solid. ¹H NMR (500 MHz, DMSO) δ 10.05 (s, 1H), 9.86 (s, 1H),7.82-7.78 (m, 3H), 7.57 (dd, J=8.3, 2.2 Hz, 1H), 7.53 (d, J=2.1 Hz, 1H),7.50 (dd, J=8.4, 2.2 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.21 (d, J=8.5 Hz,1H), 6.98 (d, J=8.4 Hz, 1H), 4.58 (br s, 2H), 4.33-4.28 (m, 4H), 3.59(t, J=5.8 Hz, 2H), 2.87 (t, J=5.9 Hz, 2H), 2.18 (s, 3H), 1.44 (s, 9H).LRMS (ESI⁺): 544.24 Example 88,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide

TFA (2 mL) was added to a suspension of Compound 31 (0.104 g, 0.191mmol) in dry DCM (3 mL) and the reaction mixture was stirred at rt for1.5 hrs, diluted with saturated NaHCO₃(aq), and the resultingprecipitate was isolated by filtration, washed with water and dried toafford the title compound (52 mg, 61%) as an off-white solid. Additionalmaterial (12 mg) was collected from the filtrate. ¹H NMR (500 MHz, DMSO)δ 10.04 (s, 1H), 9.81 (s, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.75-7.72 (m,2H), 7.56 (dd, J=8.3, 2.1 Hz, 1H), 7.53 (d, J=2.1 Hz, 1H), 7.50 (dd,J=8.4, 2.1 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 6.98(d, J=8.4 Hz, 1H), 4.33-4.28 (m, 4H), 3.96 (s, 2H), 3.03 (t, J=5.9 Hz,2H), 2.81 (t, J=5.6 Hz, 2H), 2.18 (s, 3H). HRMS (ESI⁺): calcd forC₂₆H₂₆N₃O₄ (M+H)⁺, 444.1918; found 444.1916.

Preparation of Compound 32, 4-((3-iodophenyl)amino)benzoic acid

Methanesulfonic acid (0.144 mL, 2.22 mmol) was added to a solution of6-chloronicotinic acid (0.350 g, 2.22 mmol) and 3-iodoaniline (0.487 g,2.22 mmol) in dry dioxane (5.5 mL). A thick ppt formed. The reactionmixture was heated at reflux overnight, cooled to rt, concentrated,diluted with 1 M NaOH and water, washed with DCM (2×). The aqueous phasewas acidified to pH 3-4 with 2 M HCl, and the resulting precipitate wasisolated by filtration, washed with water and dried to afford the titlecompound (647 mg, 86%) as a white solid. ¹H NMR (500 MHz, DMSO) δ 12.75(br s, 1H), 9.66 (s, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.20 (t, J=1.8 Hz,1H), 8.01 (dd, J=8.7, 2.4 Hz, 1H), 7.71 (ddd, J=8.2, 2.1, 0.8 Hz, 1H),7.31 (ddd, J=7.7, 1.5, 0.9 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 6.88-6.84(m, 1H). LRMS (ESI⁺): 340.97.

Preparation of Compound 33,6-bromo-2-((1-methylpiperidin-4-yl)oxy)quinoline

This was prepared as for Compound 3, substituting4-hydroxy-1-methylpiperidine for (R)-(−)-1-methyl-3-hydroxypyrrolidine.The crude material was purified by silica gel column chromatographyusing a gradient of 4-13% MeOH in DCM to afford the title compound as anoff-white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.87 (d, J=8.8 Hz, 1H), 7.84(ap t, J=1.4 Hz, 1H), 7.67-7.65 (m, 2H), 6.89 (d, J=8.9 Hz, 1H),5.35-5.28 (m, 1H), 2.79-2.71 (m, 2H), 2.40-4.32 (m, 2H), 2.34 (s, 3H),2.16-2.09 (m, 2H), 1.94-1.86 (m, 2H). HRMS (ESI⁺): calcd forC₁₅H₁₈79BrN₂O (M+H)⁺, 321.0597; found 321.0597.

Preparation of Compound 34,2-((1-methylpiperidin-4-yl)oxy)quinoline-6-carboxylic acid hydrochloride

This was prepared as for Compound 4, substituting Compound 33 forCompound 3 to afford the title compound as an off-white solid. ¹H NMR(500 MHz, DMSO) δ 13.10 (v br s, 1H), 11.07 (br s, 0.5H), 10.90 (br s,0.5H), 8.58-8.56 (m, 1H), 8.48-8.43 (m, 1H), 8.17-8.12 (m, 1H),7.83-7.78 (m, 1H), 7.13-7.08 (m, 1H), 5.57-5.53 (m, 0.5H), 5.46-5.38 (m,0.5H), 3.36-3.13 (m, 4H), 2.78-2.73 (m, 3H), 2.38-2.32 (m, 1H),2.30-2.17 (m, 2H), 2.10-2.00 (m, 1H). Note: this ¹H NMR spectrum shows amixture of isomers in ˜1:1 ratio; The peaks coalesce at 395 K. LRMS(ESI⁺): 287.14.

Preparation of Compound 35,3-((6-bromoquinolin-2-yl)oxy)-N,N-dimethylpropan-1-amine

This was prepared as for Compound 3, substituting3-dimethylamino-1-propanol for (R)-(−)-1-methyl-3-hydroxypyrrolidine.The crude material was purified by silica gel column chromatographyusing a gradient of 3-6% MeOH in DCM to afford the title compound as apale orange solid. ¹H NMR (500 MHz, CDCl₃) δ 7.87 (d, J=8.9 Hz, 1H),7.85-7.84 (m, 1H), 7.70-7.64 (m, 2H), 6.90 (d, J=8.9 Hz, 1H), 4.50 (t,J=6.6 Hz, 2H), 2.47 (t, J=6.6 Hz, 2H), 2.27 (s, 6H), 2.00 (p, J=6.7 Hz,2H). HRMS (ESI⁺): calcd for C₁₄H₁₈ ⁷⁹BrN₂O (M+H)⁺, 309.0597; found309.0596.

Preparation of Compound 36,2-(3-(dimethylamino)propoxy)quinoline-6-carboxylic acid hydrochloride

This was prepared as for Compound 4, substituting Compound 35 forCompound 3 to afford the title compound as a white solid. ¹H NMR (500MHz, DMSO) δ 13.07 (v br s, 1H), 10.84 (br s, 1H), 8.57 (d, J=1.9 Hz,1H), 8.44 (d, J=8.8 Hz, 1H), 8.14 (dd, J=8.7, 2.0 Hz, 1H), 7.82 (d,J=8.7 Hz, 1H), 7.10 (d, J=8.9 Hz, 1H), 4.52 (t, J=6.2 Hz, 2H), 3.26-3.19(m, 2H), 2.76 (d, J=4.9 Hz, 6H), 2.27-2.18 (m, 2H). HRMS (ESI⁺): calcdfor C₁₅H₁₉N₂O₃ (M+H)⁺, 275.1390; found 275.1393.

Preparation of Compound 37,6-bromo-2-(3-(piperidin-1-yl)propoxy)quinoline

This was prepared as for Compound 3, substituting 1-piperidinepropanolfor (R)-(−)-1-methyl-3-hydroxypyrrolidine. The crude material waspurified by silica gel column chromatography using a gradient of 2.5-6%MeOH in DCM to afford the title compound as a pale yellow solid. ¹H NMR(500 MHz, CDCl₃) δ 7.87 (d, J=8.8 Hz, 1H), 7.84 (d, J=1.9 Hz, 1H),7.70-7.64 (m, 2H), 6.89 (d, J=8.8 Hz, 1H), 4.49 (t, J=6.5 Hz, 2H),2.54-2.49 (m, 2H), 2.44 (br s, 4H), 2.04 (p, J=6.7 Hz, 2H), 1.64-1.58(m, 4H), 1.45 (br s, 2H). HRMS (ESI⁺): calcd for C₁₇H₂₂ ⁷⁹BrN₂O (M+H)⁺,349.0910; found 349.0911.

Preparation of Compound 38,2-(3-(piperidin-1-yl)propoxy)quinoline-6-carboxylic acid hydrochloride

This was prepared as for Compound 4, substituting Compound 37 forCompound 3 to afford the title compound as a pale yellow solid. ¹H NMR(500 MHz, DMSO) δ 13.05 (v br s, 1H), 10.72 (br s, 1H), 8.57 (d, J=1.9Hz, 1H), 8.44 (d, J=8.9 Hz, 1H), 8.14 (dd, J=8.7, 2.0 Hz, 1H), 7.81 (d,J=8.7 Hz, 1H), 7.09 (d, J=8.9 Hz, 1H), 4.52 (t, J=6.2 Hz, 2H), 3.44 (brd, J=11.8 Hz, 2H), 3.21-3.15 (m, 2H), 2.91-2.82 (m, 2H), 2.32-2.25 (m,2H), 1.90-1.65 (m, 6H). HRMS (ESI⁺): calcd for C₁₈H₂₃N₂O₃ (M+H)⁺,315.1703; found 315.1699.

Preparation of Compound 39, 6-bromo-2-(2-methoxyethoxy)quinoline

This was prepared as for Compound 3, substituting 2-methoxyethanol for(R)-(−)-1-methyl-3-hydroxypyrrolidine. The reaction mixture was dilutedwith water causing the title compound to precipitate as an off-whitesolid and was used without further purification. ¹H NMR (500 MHz, CDCl₃)δ 7.89 (d, J=8.9 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.71-7.65 (m, 2H),6.98 (d, J=8.9 Hz, 1H), 4.66-4.61 (m, 2H), 3.83-3.77 (m, 2H), 3.46 (s,3H). HRMS (ESI⁺): calcd for C₁₂H₁₃ ⁷⁹BrN₂O (M+H)⁺, 282.0124; found282.0130.

Preparation of Compound 40, 2-(2-methoxyethoxy)quinoline-6-carboxylicacid

This was prepared as for Compound 4, substituting Compound 39 forCompound 3 to afford the title compound as a pale pink solid. ¹H NMR(500 MHz, CDCl₃) δ 8.55 (d, J=1.9 Hz, 1H), 8.27 (dd, J=8.7, 2.0 Hz, 1H),8.09 (d, J=8.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.9 Hz, 1H),4.72-4.67 (m, 2H), 3.85-3.81 (m, 2H), 3.48 (s, 2H). HRMS (ESI⁺): calcdfor C₁₃H₁₄NO₄ (M+H)⁺, 248.0917; found 248.0918.

Preparation of Compound 41,(S)-6-bromo-2-((1-methylpyrrolidin-2-yl)methoxy)quinoline

This was prepared as for Compound 3, substituting(S)-(−)-1-methyl-2-pyrrolidinemethanol for(R)-(−)-1-methyl-3-hydroxypyrrolidine. The crude material was purifiedby silica gel column chromatography using a gradient of 3-7% MeOH in DCMto afford the title compound as a pale orange oil. ¹H NMR (500 MHz,CDCl₃) δ 7.88 (d, J=8.9 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.70-7.64 (m,2H), 6.95 (d, J=8.9 Hz, 1H), 4.52 (dd, J=11.0, 5.1 Hz, 1H), 4.42 (dd,J=11.0, 5.1 Hz, 1H), 3.14 (t, J=8.0 Hz, 1H), 2.71-2.65 (m, 1 OH), 2.51(s, 3H), 2.34-2.26 (m, 1H), 2.07-1.96 (m, 1H), 1.91-1.72 (m, 3H). HRMS(ESI⁺): calcd for C₁₅H₁₈ ⁷⁹BrN₂O (M+H)⁺, 321.0597; found 321.0585.

Preparation of Compound 42,(S)-2-((1-methylpyrrolidin-2-yl)methoxy)quinoline-6-carboxylic acidhydrochloride

This was prepared as for Compound 4, substituting Compound 41 forCompound 3 to afford the title compound as a pale yellow solid. ¹H NMR(500 MHz, DMSO) δ 13.09 (v br s, 1H), 11.37 (br s, 1H), 8.59 (d, J=1.9Hz, 19H), 8.48 (d, J=8.7 Hz, 1H), 8.16 (dd, J=8.7, 2.0 Hz, 1H), 7.85 (d,J=8.7 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 4.85-4.78 (m, 2H), 3.91-3.84 (m,1H), 3.63-3.54 (m, 1H), 3.15-3.06 (m, 1H), 2.94 (d, J=4.9 Hz, 3H),2.35-2.25 (m, 1H), 2.08-1.83 (m, 3H). HRMS (ESI⁺): calcd for C₁₆H₁₉N₂O₃(M+H)⁺, 287.1390; found 287.1390.

Preparation of Compound 43,6-bromo-2-(2-(piperidin-1-yl)ethoxy)quinoline

This was prepared as for Compound 3, substituting4-(2-hydroxyethyl)piperidine for (R)-(−)-1-methyl-3-hydroxypyrrolidine.The crude material was purified by silica gel column chromatographyusing a gradient of 4-5% MeOH in DCM to afford the title compound as apale yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.87 (d, J=8.9 Hz, 1H), 7.85(d, J=1.9 Hz, 1H), 7.70-7.64 (m, 2H), 6.93 (d, J=8.9 Hz, 1H), 4.60 (t,J=6.1 Hz, 2H), 2.81 (t, J=6.0 Hz, 2H), 2.53 (br s, 4H), 1.65-1.68 (m,4H), 1.48-1.42 (m, 2H). HRMS (ESI⁺): calcd for C₁₆H₂₀ ⁷⁹BrN₂O (M+H)⁺,335.0754; found 335.0755.

Preparation of Compound 44,2-(2-(piperidin-1-yl)ethoxy)quinoline-6-carboxylic acid hydrochloride

This was prepared as for Compound 4, substituting Compound 43 forCompound 3 to afford the title compound as an off-white solid. ¹H NMR(500 MHz, DMSO) δ 13.10 (v br s, 1H), 10.99 (br s, 1H), 8.59 (d, J=1.9Hz, 1H), 8.47 (d, J=8.9 Hz, 1H), 8.16 (dd, J=8.7, 2.0 Hz, 1H), 7.85 (d,J=8.7 Hz, 1H), 7.16 (d, J=8.9 Hz, 1H), 4.89-4.82 (m, 2H), 3.58-3.46 (m,4H), 3.05-2.96 (m, 2H), 1.88-1.64 (m, 4H). HRMS (ESI⁺): calcd forC₁₇H₂₁N₂O₃ (M+H)⁺, 301.1547; found 301.1535.

Preparation of Compound 45, 2-oxo-2H-chromene-6-carboxylic acid

Water (0.65 mL) was added to 62.5% H₂SO₄ (3.05 mL), followed by6-methylcoumarin (0.500 g, 3.12 mmol), and chlorobenzene (0.5 mL). Thereaction mixture was heated to 85° C. and then manganese(IV) oxide(0.800 g, 9.20 mmol) was added portion-wise, followed by 62.5% H₂SO₄(0.4 mL). The reaction mixture was stirred for 30 min at 85° C., cooledto rt, added water (2.9 mL), followed by NH₃(aq) (25%, 0.85 mL)dropwise. Next EtOAc (8 mL) was added and the aqueous layer was removedand extracted with a small amount of EtOAc, and the combined organiclayers were washed with a small amount of water. To the organic phasewas added DMSO (0.3 mL), followed by 25% NH₃(aq) (0.2 mL) dropwise. Thereaction mixture was heated to 30-40° C., and then sodium chlorite (80%,solution of 25% in water, 1.125 mL, 3.12 mmol) was added dropwise. Ther×n mix was stirred at 40° C. for 1 hr, then 25% NH₃(aq) (0.27 mL) wasadded, and the phases were separated. To the aqueous layer was addedMeOH (1.5 mL), HCl (0.1 mL), and then heated to 30° C. before sodiumsulfite (0.039 g, 3.1 mmol) was added. The reaction mixture was stirredat 30° C. for 25 min, and then heated to 45° C. before HCl (0.5 mL) wasadded dropwise. The r×n mixture was then cooled in an ice bath, and theresulting solid collected by filtration, washed with water and dried toafford the title compound (25 mg, 4%) as a dull orange solid. ¹H NMR(500 MHz, DMSO) δ 13.23 (br s, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.20 (d,J=9.4 Hz, 1H), 8.12 (dd, J=8.6, 2.1 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H),6.59 (d, J=9.6 Hz, 1H). HRMS (ESI⁺): calcd for C₁₀H₇O₄ (M+H)⁺, 191.0339;found 191.0341.

Preparation of Compound 46,4-(3-((6-bromoquinolin-2-yl)oxy)propyl)morpholine

This was prepared as for Compound 3, substituting4-(3-hydroxypropyl)morpholine for (R)-(−)-1-methyl-3-hydroxypyrrolidine.The crude material was purified by silica gel column chromatographyusing a gradient of 1.5-3.5% MeOH in DCM to afford the title compound asa white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.88 (d, J=8.9 Hz, 1H),7.86-7.84 (m, 1H), 7.69-7.65 (m, 2H), 6.90 (d, J=8.9 Hz, 1H), 4.51 (t,J=6.5 Hz, 2H), 3.73 (t, J=4.6 Hz, 4H), 2.57-2.53 (m, 2H), 2.49 (br s,4H), 2.06-1.98 (m, 2H). HRMS (ESI⁺): calcd for C₁₆H₂₀ ⁷⁹BrN₂O₂(M+H)⁺,351.0703; found 351.0712.

Preparation of Compound 47,2-(3-morpholinopropoxy)quinoline-6-carboxylic acid hydrochloride

This was prepared as for Compound 4, substituting Compound 46 forCompound 3 to afford the title compound as a pale yellow solid. ¹H NMR(500 MHz, DMSO) δ 11.54 (br s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.44 (d,J=8.9 Hz, 1H), 8.14 (dd, J=8.7, 1.9 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H),7.10 (d, J=8.9 Hz, 1H), 4.53 (t, J=6.2 Hz, 2H), 3.97-3.92 (m, 2H),3.91-3.81 (m, 2H), 3.45 (d, J=12.3 Hz, 2H), 3.31-3.23 (m, 2H), 3.12-3.02(m, 2H), 2.34-2.25 (m, 2H). HRMS (ESI⁺): calcd for C₁₇H₂₁N₂O₄ (M+H)⁺,317.1496; found 317.1501.

Preparation of Compound 48,⁵ 3-(pyrrolidin-1-yl)propan-1-ol

Pyrrolidine (1.00 mL, 12.0 mmol) was added to a suspension of potassiumcarbonate (1.29 g, 9.35 mmol) and 3-bromopropanol (0.65 mL, 7.2 mmol) indry THF (3 mL) at 0° C. The reaction mixture was then allowed to warm tort, stirred overnight, diluted with EtOAc, filtered through a silica padand the filtrate concentrated to afford the title compound (645 mg, 69%)as a colourless oil. ¹H NMR (500 MHz, CDCl₃) δ 5.54 (br s, 1H),3.84-3.77 (m, 2H), 2.77-2.68 (m, 2H), 2.60-2.53 (m, 4H), 1.80-1.68 (m,6H). LRMS (ESI⁺) (M+H)+: 130.12

Preparation of Compound 49,6-bromo-2-(3-(pyrrolidin-1-yl)propoxy)quinoline

This was prepared as for Compound 3, substituting Compound 48 for(R)-(−)-1-methyl-3-hydroxypyrrolidine. The crude material was purifiedby silica gel column chromatography using a gradient of 3-3.6% MeOH inDCM to afford the title compound as an off-white solid. ¹H NMR (500 MHz,CDCl₃) δ 7.87 (d, J=8.8 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.70-7.64 (m,2H), 6.90 (d, J=8.9 Hz, 1H), 4.51 (t, J=6.5 Hz, 2H), 2.70-2.62 (m, 2H),2.56 (br s, 4H), 2.11-2.01 (m, 2H), 1.83-1.78 (m, 4H). HRMS (ESI⁺):calcd for C₁₆H₂₀ ⁷⁹BrN₂O (M+H)⁺, 335.0754; found 335.0749.

Preparation of Compound 50,2-(3-(pyrrolidin-1-yl)propoxy)quinoline-6-carboxylic acid hydrochloride

This was prepared as for Compound 4, substituting Compound 49 forCompound 3 to afford the title compound as a pale yellow solid. ¹H NMR(500 MHz, DMSO) δ 10.84 (br s, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.44 (d,J=8.8 Hz, 1H), 8.14 (dd, J=8.7, 2.0 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H),7.10 (d, J=8.9 Hz, 1H), 4.53 (t, J=6.2 Hz, 2H), 3.57-3.52 (m, 2H),3.34-3.26 (m, 2H), 3.04-2.95 (m, 2H), 2.27-2.19 (m, 2H), 2.01-1.97 (m,2H), 1.92-1.85 (m, 2H). HRMS (ESI⁺): calcd for C₁₇H₂₁N₂O₄ (M+H)⁺,301.1547; found 301.1549.

Preparation of Compound 51, tert-butyl(2-((6-bromoquinolin-2-yl)oxy)ethyl)carbamate

This was prepared as for Compound 3, substituting tert-butylN-(2-hydroxyethyl)carbamate for (R)-(−)-1-methyl-3-hydroxypyrrolidine.The crude material was purified by silica gel column chromatographyusing a gradient of 20-25% diethyl ether in PE to afford the titlecompound as a white solid. ¹H NMR (500 MHz, DMSO) b 8.22 (d, J=8.9 Hz,1H), 8.17 (d, J=2.3 Hz, 1H), 7.77 (dd, J=8.9, 2.3 Hz, 1H), 7.69 (d,J=8.9 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 7.03 (t, J=5.7 Hz, 1H), 4.39 (t,J=5.7 Hz, 2H), 3.36 (q, J=5.8 Hz, 2H), 1.37 (s, 9H). HRMS (ESI⁺): calcdfor C₁₆H₂₀ ⁷⁹BrN₂O₃(M+H)⁺, 367.0652; found 367.0649.

Preparation of Compound 52,2-(2-((tert-butoxycarbonyl)amino)ethoxy)quinoline-6-carboxylic acid

This was prepared as for Compound 4, substituting Compound 51 forCompound 3, and using 2.2 equivalents of nBuLi. In the work-up, when theaqueous solution was acidified, no precipitate formed, and thus theaqueous layer was extracted with DCM (3×), and this organic phase wasdried over MgSO₄, filtered and concentrated to afford the title compoundas a white solid. ¹H NMR (500 MHz, DMSO) δ 13.06 (br s, 1H), 8.56 (d,J=1.9 Hz, 1H), 8.41 (d, J=8.9 Hz, 1H), 8.13 (dd, J=8.7, 2.0 Hz, 1H),7.80 (d, J=8.8 Hz, 1H), 7.07 (d, J=8.9 Hz, 1H), 7.04 (t, J=5.7 Hz, 1H),4.43 (t, J=5.8 Hz, 2H), 3.37 (q, J=5.6 Hz, 2H), 1.37 (s, 9H). HRMS(ESI⁺): calcd for C₁₇H₂₁N₂O₅ (M+H)⁺, 333.1445; found 333.1447.

Preparation of Compound 53, 2-(3-fluoropiperidin-1-yl)ethanol

2-Bromoethanol (0.184 mL, 2.60 mmol) was added to a suspension of3-fluoropiperidine hydrochloride (0.352 g, 2.52 mmol) and potassiumcarbonate (0.767 g, 5.55 mmol) in dry acetonitrile (5.5 mL) and thereaction mixture was heated at reflux overnight, cooled to rt, filtered,concentrated, added diethyl ether, extracted with 1 M HCl (2×). Theaqueous phase was made basic (pH>12) with solid NaOH, then extractedwith DCM (3×). This organic phase was dried over K₂CO₃, filtered andconcentrated to afford the title compound (201 mg, 54%), as a paleyellow oil. ¹H NMR (500 MHz, CDCl₃) δ 4.83-4.69 (m, 1H), 3.75-3.68 (m,2H), 3.02-2.94 (m, 1H), 2.76-2.63 (m, 4H), 2.57-2.50 (m, 1H), 1.98-1.85(m, 2H), 1.76-1.61 (m, 2H). HRMS (ESI⁺): calcd for C₇H₁₅FNO (M+H)⁺,148.1132; found 148.1138.

Preparation of Compound 54,6-bromo-2-(2-(3-fluoropiperidin-1-yl)ethoxy)quinoline

This was prepared as for Compound 3, substituting Compound 53 for(R)-(−)-1-methyl-3-hydroxypyrrolidine. The crude material was purifiedby silica gel column chromatography using a gradient of 1 to 1.75% MeOHin DCM to afford the title compound as a very pale yellow oil. ¹H NMR(500 MHz, CDCl₃) δ 7.90 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.70-7.67 (m,2H), 6.94 (d, J=8.9 Hz, 1H), 4.71 (v br s, 3H), 3.01 (v br s, 3H), 2.68(v br s, 3H), 1.92 (v br s, 2H), 1.67 (v br s, 2H). HRMS (ESI⁺): calcdfor C₁₆H₁₉ ⁷⁹BrFN₂O (M+H)⁺, 353.0659; found 353.0654.

Preparation of Compound 55,2-(2-(3-fluoropiperidin-1-yl)ethoxy)quinoline-6-carboxylic acidhydrochloride

This was prepared as for Compound 4, substituting Compound 54 forCompound 3 to afford the title compound as an off-white solid. ¹H NMR(500 MHz, DMSO) δ 13.11 (v br s, 1H), 11.75 (br s, 0.3H), 10.47 (br s,0.7H), 8.61-8.58 (m, 1H), 8.51-8.46 (m, 1H), 8.19-8.14 (m, 1H),7.87-7.83 (m, 1H), 7.19-7.14 (m, 1H), 5.18-5.05 (m, 1H), 4.90-4.81 (m,2H), 3.87-3.10 (m, 6H), 2.06-1.59 (m, 4H). Note: this is a mixture ofisomers in ˜7:3 ratio. HRMS (ESI⁺): calcd for C₁₇H₂₀FN₂O₃(M+H)⁺,319.1452; found 319.1454.

Preparation of Compound 56, methyl 2-chloroquinoline-6-carboxylate andCompound 57, methyl 4-chloroquinoline-6-carboxylate

3-Chloroperbenzoic acid (3.20 g, 13.9 mmol) was added to a solution ofmethyl 6-quinolinecarboxylate (2.000 g, 10.68 mmol) in dry DCM (31 mL)at 0° C. The reaction mixture was then allowed to warm to rt, andstirred overnight. The reaction mixture was then diluted with DCM andwashed with 10% sodium sulfite(aq) (1×). The aqueous phase was extractedwith DCM (1×), and the combined organic phases were washed withsaturated NaHCO₃(aq) (1×), brine (1×), dried (MgSO₄), filtered andconcentrated to afford the 6-(methoxycarbonyl)quinoline 1-oxideintermediate as a tan coloured solid. The N-oxide intermediate (2.07 g)was dissolved in dry DCM (27 mL), and to this was added phosphorusoxychloride (13.25 mL, 142.0 mmol) slowly while cooling the flask in awater bath. After the addition the water bath was removed and thereaction mixture was heated to 50° C. overnight, cooled to rt,concentrated, diluted with EtOAc, washed with saturated NaHCO₃ (3×). Theaqueous phase was made basic with 1 M NaOH, then extracted with EtOAc(1×). The combined organic phases were washed with brine (1×), dried(MgSO₄), filtered and concentrated. The crude material was purified bysilica gel column chromatography using a gradient of 10 to 3% PE intoluene and then switching to a gradient of 5 to 10% EtOAc in toluene.The first to elute was Compound 56 (458 mg, 20%) as an off-white solidfollowed by Compound 57 (1.146, 51%) as a pale yellow solid.

Compound 56: ¹H NMR (500 MHz, CDCl₃) δ 8.59 (d, J=1.9 Hz, 1H), 8.33 (dd,J=8.8, 1.9 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.06 (ap dt, J=8.8, 0.7 Hz,1H), 7.47 (d, J=8.6 Hz, 1H), 4.00 (s, 3H). HRMS (ESI⁺): calcd forC₁₁H₉ClNO₂ (M+H)⁺, 222.0316; found 222.0321.

Compound 57: ¹H NMR (500 MHz, CDCl₃) δ 8.98 (dd, J=1.9, 0.6 Hz, 1H),8.87 (d, J=4.7 Hz, 1H), 8.36 (dd, J=8.7, 1.9 Hz, 1H), 8.17 (dd, J=8.9,0.7 Hz, 1H), 7.57 (d, J=4.7 Hz, 1H), 4.02 (s, 3H).

Preparation of Compound 58, methyl2-((2-(dimethylamino)ethyl)(methyl)amino)quinoline-6-carboxylate

A solution Compound 56 (0.084 g, 0.38 mmol),N,N,N′-trimethylethylenediamine (0.077 g, 0.76 mmol, andN,N-diisopropylethylamine (0.13 mL, 0.76 mmol) in dry dioxane (2.0 mL)was heated in the microwave at 150° C. for 3 hours, cooled,concentrated, diluted with EtOAc, washed with water (1×), brine (1×),dried (Na₂SO₄), filtered and concentrated. The residue was purified bysilica gel column chromatography using a gradient of 5 to 16% MeOH inDCM to afford the title compound (90 mg, 83%) as an off-white solid. ¹HNMR (500 MHz, CDCl₃) δ 8.33 (d, J=2.0 Hz, 1H), 8.10 (dd, J=8.8, 2.0 Hz,1H), 7.90 (d, J=9.1 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 6.90 (d, J=9.2 Hz,1H), 3.94 (s, 3H), 3.83 (t, J=7.4 Hz, 2H), 3.24 (s, 3H), 2.58 (t, J=7.4Hz, 2H), 2.35 (s, 6H). HRMS (ESI⁺): calcd for C₁₆H₂₂N₃O₂ (M+H)⁺,288.1706; found 288.1710.

Preparation of Compound 59,2-((2-(dimethylamino)ethyl)(methyl)amino)quinoline-6-carboxylic acidhydrochloride

An aqueous solution of NaOH (0.95 M, 1.93 mL, 1.84 mmol) was added to asolution of Compound 58 (0.088 g, 0.31 mmol) in THF (2.0 mL), followedby MeOH (0.5 mL) and the reaction mixture was stirred at rt overnight,concentrated to remove organic solvents, diluted with water, and washedwith EtOAc (1×). The aqueous phase was acidified with 2 M HCl to ˜pH 3,then concentrated to dryness and used without further purification(contains NaCl). ¹H NMR (500 MHz, DMSO) δ 10.73 (v br s, 1H), 8.49 (brs, 1H), 8.41 (br s, 1H), 8.18-8.08 (m, 2H), 7.43 (br s, 1H), 4.21 (br s,2H), 2.86 (s, 6H). Note that the other signals are hidden underneath thelarge water peak. HRMS (ESI⁺): calcd for C_(1s)H₂₀N₃O₂ (M+H)⁺, 274.1550;found 274.1549.

Preparation of Compound 60, methyl2-(2-(pyrrolidin-1-yl)ethyl)quinoline-6-carboxylate

A solution of pyrrolidine (0.082 mL, 0.99 mmol), hydrochloric acid (32%,0.097 mL, 0.99 mmol) and formaldehyde solution, (37%, 0.074 mL, 0.99mmol) was carefully made, and then added to a slurry of methyl2-methylquinoline-6-carboxylate (0.400 g, 1.99 mmol) in MeOH (0.5 mL),The reaction mixture was then heated to 50° C. for 3 hrs and 20 min,cooled to rt diluted with water, the pH was adjusted to 3-4 with 2 MHCl, washed with EtOAc (2×). The aqueous phase was made basic with 2 MNaOH, then extracted with DCM (2×). This organic phase was dried(Na₂SO₄), filtered and concentrated. The crude material was purified bysilica gel column chromatography using a gradient of 5 to 11% MeOH inDCM to afford the title compound (166 mg, 59%) as a pale purple solid.¹H NMR (500 MHz, CDCl₃) δ 8.56 (d, J=1.8 Hz, 1H), 8.28 (dd, J=8.8, 1.9Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.4Hz, 1H), 3.99 (s, 3H), 3.60-3.35 (br m, 4H), 2.99 (br s, 4H), 2.03 (brs, 4H). HRMS (ESI⁺): calcd for C₁₇H₂₁N₂O₂ (M+H)⁺, 285.1598; found285.1599.

Preparation of Compound 61, methyl2-(2-(pyrrolidin-1-yl)ethyl)quinoline-6-carboxylate hydrochloride

LiOH (0.99 M, 0.245 mL, 0.24 mmol) was added to a solution of Compound60 (0.034 g, 0.12 mmol) in THF (1.5 mL), followed by MeOH (0.3 mL). Appt appeared and so additional water (0.20 mL) was added and thereaction mixture was stirred at rt for 23.5 hrs, concentrated to removeorganic solvents, diluted with water, washed with EtOAc (1×). Theaqueous phase was acidified to pH 3 with 2 M HCl, and then concentratedto dryness to afford the title compound as a white solid (contains LiCl)which was used without further purification. HRMS (ESI⁺): calcd forC₁₆H₁₉N₂O₂ (M+H)⁺, 271.1441; found 271.1442.

Preparation of Compound 62,^(6,7) 2-(azetidin-1-yl)ethanol

Triethylamine (0.271 mL, 1.93 mmol) was added to a solution of azetidine(0.118 mL, 1.75 mmol) in dry DCM (3.6 mL). The reaction mixture wasstirred for 30 min at rt, before acetoxyacetyl chloride (0.188 mL, 1.75mmol) was added slowly dropwise, while the flask was cooled in a waterbath. A ppt formed during the addition. The reaction mixture was stirredat rt overnight, filtered, and the filtrate was washed with water (1×),dried (Na₂SO₄), filtered and concentrate, leaving the intermediate 32-(azetidin-1-yl)-2-oxoethyl acetate as a very pale yellow oil. Asolution of this intermediate (0.275 g, 1.75 mmol) in dry THF (2.9 mL)was added dropwise to LiAlH₄ (1 M in THF, 1.925 mL, 1.925 mmol) at 0° C.over 5 min. The reaction mixture was then allowed to warm to rt andstirred for 1 hr 40 min, after which time water (73 uL) was addeddropwise while the reaction flask was cooled in a water batch, followedby 10% NaOH(aq) (73 uL), and 4-5 mL Et₂O and the mixture was thenstirred at rt for 1 hour. Water (219 uL) was then added and the mixturefiltered through celite with Et₂O, and the filtrate was concentrated toafford the title compound (135 mg, 76%) as a colourless oil. ¹H NMR (500MHz, DMSO) δ 4.32 (t, J=5.5 Hz, 1H), 3.29 (q, J=6.0 Hz, 2H), 3.08 (t,J=6.9 Hz, 4H), 2.37 (t, J=6.3 Hz, 2H), 1.92 (p, J=6.9 Hz, 2H). HRMS(ESI⁺): calcd for C₅H₁₂NO (M+H)⁺, 102.0913; found 102.0912.

Preparation of Compound 63, 2-(2-(azetidin-1-yl)ethoxy)-6-bromoquinoline

This was prepared as for Compound 3, substituting Compound 62 for(R)-(−)-1-methyl-3-hydroxypyrrolidine. The crude material was purifiedby silica gel column chromatography using a gradient of 2 to 6% MeOH inDCM to afford the title compound as a very pale yellow oil. ¹H NMR (500MHz, CDCl₃) δ 7.87 (d, J=8.9 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.70-7.64(m, 2H), 6.94 (d, J=8.9 Hz, 1H), 4.47-4.43 (m, 2H), 3.34 (t, J=7.0 Hz,4H), 2.87 (t, J=5.5 Hz, 2H), 2.13 (p, J=7.1 Hz, 2H). HRMS (ESI⁺): calcdfor C₁₄H₁₆ ⁷⁹BrN₂O (M+H)⁺, 307.0440; found 307.0438.

Preparation of Compound 64,2-(2-(azetidin-1-yl)ethoxy)quinoline-6-carboxylic acid hydrochloride

This was prepared as for Compound 4, substituting Compound 63 forCompound 3 to afford the title compound as a pale yellow solid. ¹H NMR(500 MHz, DMSO) δ 13.12 (v br s, 1H), 11.20 (br s, 1H), 8.59 (d, J=2.0Hz, 1H), 8.47 (d, J=8.9 Hz, 1H), 8.16 (dd, J=8.7, 2.0 Hz, 1H), 7.84 (d,J=8.7 Hz, 1H), 7.14 (d, J=8.9 Hz, 1H), 4.69-4.62 (m, 2H), 4.16-4.10 (m,4H), 3.68-3.57 (m, 2H), 2.45-2.35 (m, 1H), 2.30-2.22 (m, 1H). HRMS(ESI⁺): calcd for C₁₅H₁₇N₂O₃(M+H)⁺, 273.1234; found 273.1236.

Preparation of Compound 65,⁸ 2-(2-methylpyrrolidin-1-yl)ethanol

2-Bromoethanol (0.255 mL, 3.59 mmol) was added to a suspension of2-methylpyrrolidine (0.360 mL, 3.52 mmol) and potassium carbonate (0.536g, 3.88 mmol) in dry cetonitrile (6.2 mL). The reaction mixture was thenheated to reflux overnight, cooled to rt, filtered to remove solids andthe filtrate was concentrated. To this was added Et₂O, extracted with 1M HCl (2×). The aqueous phase was made basic (pH>12) with solid NaOH,then extracted with DCM (3×). This organic phase was dried over K₂CO₃,filtered and concentrated to afford the title compound (351 mg, 77%) asa pale yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 3.64 (td, J=10.2, 3.7 Hz,1H), 3.60-3.54 (m, 1H), 3.15 (ddd, J=9.1, 8.0, 3.1 Hz, 1H), 2.97 (ddd,J=12.2, 9.9, 5.1 Hz, 1H), 2.81 (br s, 1H), 2.49-2.40 (m, 1H), 2.27 (dt,J=12.3, 3.4 Hz, 1H), 2.15 (q, J=8.8 Hz, 1H), 1.95-1.88 (m, 1H),1.81-1.65 (m, 2H), 1.40 (dddd, J=12.4, 10.2, 8.3, 6.1 Hz, 1H), 1.08 (d,J=6.1 Hz, 3H). HRMS (ESI⁺): calcd for C₇H₁₆NO (M+H)⁺, 130.1226; found130.1229.

Preparation of Compound 66,6-bromo-2-(2-(2-methylpyrrolidin-1-yl)ethoxy)quinoline

This was prepared as for Compound 3, substituting Compound 65 for(R)-(−)-1-methyl-3-hydroxypyrrolidine. The crude material was purifiedby silica gel column chromatography using a gradient of 3 to 8% MeOH inDCM to afford the title compound as a very pale orange solid. ¹H NMR(500 MHz, CDCl₃) δ 7.87 (d, J=8.9 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H),7.70-7.64 (m, 2H), 6.94 (d, J=8.9 Hz, 1H), 4.63-4.58 (m, 2H), 3.35-3.22(m, 2H), 2.57 (dt, J=12.0, 5.4 Hz, 1H), 2.46-2.38 (m, 1H), 2.30 (q,J=8.9 Hz, 1H), 1.98-1.89 (m, 1H), 1.88-1.78 (m, 1H), 1.77-1.68 (m, 1H),1.50-1.43 (m, 1H), 1.15 (d, J=6.0 Hz, 3H). HRMS (ESI⁺): calcd for C₁₆H₂₀⁷⁹BrN₂O (M+H)⁺, 335.0754; found 335.0753.

Preparation of Compound 67,2-(2-(2-methylpyrrolidin-1-yl)ethoxy)quinoline-6-carboxylic acidhydrochloride

This was prepared as for Compound 4, substituting Compound 66 forCompound 3 to afford the title compound as an off-white solid. ¹H NMR(500 MHz, DMSO) δ 13.10 (br s, 1H), 10.99 (br s, 1H), 8.59 (d, J=1.9 Hz,1H), 8.48 (d, J=8.9 Hz, 1H), 8.16 (dd, J=8.8, 1.9 Hz, 1H), 7.85 (d,J=8.7 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 4.85-4.81 (m, 2H), 3.81-3.75 (m,1H), 3.74-3.65 (m, 1H), 3.47 (br s, 2H), 3.25-3.18 (m, 1H), 2.22-2.12(m, 1H), 2.00-1.92 (m, 2H), 1.71-1.60 (m, 1H), 1.44 (d, J=6.5 Hz, 3H).LRMS (ESI⁺) (M+H)+: 301.29.

Preparation of Compound 68,2-(2-(dimethylamino)ethoxy)quinoline-6-carboxylic acid hydrochloride

N,N-Dimethylethanolamine (0.102 mL, 1.02 mmol) added to a suspension ofNaH (60%, 0.041 g, 1.02 mmol) in dry dioxane (1.75 mL). The reactionmixture was stirred at rt for 35 min before Compound 17 (0.060 g, 0.26mmol) was added and the reaction mixture was then heated to 60° C. for 1hr 35 min at which time additional dioxane (2.0 mL) was added to helpthe thick mixture to stir. The reaction mixture was then heated to 80°C. for 4 hrs, and then at rt overnight, diluted with water, washed withEtOAc (1×). The aqueous phase was acidified to pH 3 with 2 M HCl, andthen concentrated to afford the title compound as a white solid(contains NaCl). ¹H NMR (500 MHz, DMSO) δ 8.59 (d, J=1.9 Hz, 1H), 8.47(d, J=8.9 Hz, 1H), 8.16 (dd, J=8.7, 2.0 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H),7.16 (d, J=8.9 Hz, 1H), 4.85-4.77 (m, 2H), 3.56 (br s, 2H), 2.83 (br s,6H). HRMS (ESI⁺): calcd for C₁₄H₁₇N₂O₃ (M+H)⁺, 261.1234; found 261.1235.

Preparation of Compound 69,6-bromo-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline

This was prepared as for Compound 3, substituting4-(2-hydroxyethyl)pyrrolidine for (R)-(−)-1-methyl-3-hydroxypyrrolidine.The crude material was purified by silica gel column chromatographyusing a gradient of 3 to 6% MeOH in DCM to afford the title compound asa very pale yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.87 (d, J=8.9 Hz,1H), 7.85 (d, J=1.9 Hz, 1H), 7.72-7.63 (m, 2H), 6.96 (d, J=8.9 Hz, 1H),4.61 (t, J=5.9 Hz, 2H), 2.94 (t, J=5.9 Hz, 2H), 2.70-2.59 (m, 4H),1.86-1.77 (m, 4H). HRMS (ESI⁺): calcd for C₁₅H₁₈ ⁷⁹BrN₂O (M+H)⁺,321.0597; found 321.0587.

Preparation of Compound 70,2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxylic acid hydrochloride

This was prepared as for Compound 4, substituting Compound 69 forCompound 3 to afford the title compound as an off-white solid. ¹H NMR(500 MHz, DMSO) δ 13.12 (v br s, 1H), 11.22 (br s, 1H), 8.59 (d, J=1.9Hz, 1H), 8.48 (d, J=8.8 Hz, 1H), 8.16 (dd, J=8.7, 2.0 Hz, 1H), 7.85 (d,J=8.7 Hz, 1H), 7.18 (d, J=8.9 Hz, 1H), 4.83-4.76 (m, 2H), 3.68-3.56 (m,4H), 3.15-3.07 (m, 2H), 2.06-1.95 (m, 2H), 1.96-1.84 (m, 2H). HRMS(ESI⁺): calcd for C₁₆H₁₈N₂O₃(M+H)⁺, 287.1390; found 287.1380.

Preparation of Compound 71, methyl2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)quinoline-6-carboxylate

A solution of Compound 56 (0.103 g, 0.464 mmol),methyl[2-(pyrrolidin-1-yl)ethyl]amine (0.119 g, 0.928 mmol), andN,N-diisopropylethylamine (0.16 mL, 0.93 mmol) in dry dioxane (2.0 mL)was heated in a microwave at 150° C. for 2.5 hrs, cooled, diluted withEtOAc, washed with water (1×), brine (1×), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by silica gel columnchromatography using a gradient of 5 to 13% MeOH in DCM to afford thetitle compound (130 mg, 89%) as a pale yellow-brown solid. ¹H NMR (500MHz, CDCl₃) δ 8.37 (d, J=2.0 Hz, 1H), 8.13 (dd, J=8.8, 2.0 Hz, 1H), 7.97(d, J=9.2 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 6.95 (d, J=9.2 Hz, 1H), 4.20(br s, 2H), 3.95 (s, 3H), 2.08 (brs, 4H). The remaining protons appearedas an extremely broad hump from roughly 3.75-2.75 ppm which could not beintegrated accurately. HRMS (ESI⁺): calcd for C₁₈H₂₄N₃O₂ (M+H)⁺,314.1863; found 314.1864.

Preparation of Compound 72,2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)quinoline-6-carboxylic acidhydrochloride

NaOH (0.99 M, 2.40 mL, 2.37 mmol) was added to a suspension of Compound71 (0.124 g, 0.396 mmol) in THF (4.0 mL), followed by MeOH (1.25 mL).The reaction mixture was stirred at rt overnight, concentrated to removeorganic solvents, washed with EtOAc (1×). The aqueous phase wasacidified to pH 3 with 2 M HCl, then concentrated to dryness to affordthe title compound as an off-white solid (contains NaCl). ¹H NMR (500MHz, DMSO) δ 13.09, (v br s, 1H), 11.15 (v br s, 1H), 8.49 (br s, 1H),4.40 (br s, 1H), 8.13 (br s, 1H), 7.44 (v br s, 2hH), 4.20 (br s, 2H),3.88 (br s, 4H), 3.56 (br s, 2H), 3.47 (br s, 3H), 3.12 (br s, 2H),2.11-1.76 (br m, 4H). HRMS (ESI⁺): calcd for C₁₇H₂₂N₃O₂ (M+H)⁺,300.1706; found 300.1705.

Preparation of Compound 73, (R)-2-(3-hydroxypyrrolidin-1-yl)ethylacetate

2-Bromoethyl acetate (1.535 mL, 13.54 mmol) was added dropwise to amixture of (R)-3-hydroxypyrrolidine HCl (1.568 g, 12.31 mmol) andpotassium carbonate (5.10 g, 36.9 mmol) in dry acetonitrile (35 mL) andthe reaction mixture was heated at reflux for 6.5 hrs, cooled, filtered(washed through with EtOAc), and the filtrate was concentrated, dilutedwith DCM, and washed with water (1×). The aqueous phase was extractedwith DCM (3×). The combined organic phases were dried (MgSO4), filteredand concentrated to afford the title compound (1.364 g, 64%) as acolourless oil. ¹H NMR (500 MHz, CDCl₃) δ 4.36-4.32 (m, 1H), 4.19 (t,J=5.7 Hz, 2H), 2.93 (td, J=8.6, 5.2 Hz, 1H), 2.77-2.70 (m, 3H), 2.59(dd, J=10.0, 5.1 Hz, 1H), 2.36 (td, J=8.9, 6.3 Hz, 1H), 2.18 (dddd,J=13.9, 8.7, 7.1, 5.2 Hz, 1H), 2.07 (s, 3H), 1.79-1.71 (m, 1H). HRMS(ESI⁺): calcd for C₈H₁₆NO₃ (M+H)⁺, 174.1125; found 174.1128.

Preparation of Compound 74, (S)-2-(3-fluoropyrrolidin-1-yl)ethyl acetate

N,N-Diethylaminosulfur trifluoride (2.58 ml, 19.5 mmol) was addeddropwise to a solution of Compound 73 (1.35 g, 7.81 mmol) in dry DCM (35ml) at −78° C. Upon completion of the addition, the reaction mixture wasallowed to warm to rt and stirred for 3 hrs, then cooled to −5 to −10°C., and quenched with MeOH, washed with saturated NaHCO₃(aq) (2×). Added1 M NaOH to the aqueous phase to insure pH>10, then extracted with DCM(3×). The combined organic phases were dried (MgSO₄), filtered andconcentrated. The crude material was purified by silica gel columnchromatography using a gradient of 1 to 4% MeOH in DCM to afford thetitle compound (418 mg, 31%) as a brown oil. ¹H NMR (500 MHz, CDCl₃) δ5.17 (dddt, J=55.6, 6.6, 5.0, 1.8 Hz, 1H), 4.20 (t, J=5.9 Hz, 2H),2.95-2.72 (m, 5H), 2.56-2.50 (m, 1H), 2.20-1.98 (m, 2H), 2.07 (3H, s).HRMS (ESI⁺): calcd for C₈H₁₅FNO₂ (M+H)⁺, 176.1081; found 176.1084.

Preparation of Compound 75, (S)-2-(3-fluoropyrrolidin-1-yl)ethanol

A catalytic amount of NaOMe (enough to make the solution basic) wasadded to a solution of Compound 74 (0.416 g, 2.37 mmol) in dry MeOH (15mL) The reaction mixture was stirred overnight at rt, concentrated, andthe residue dissolved in DCM, washed with saturated NaHCO₃(aq) (1×). Theaqueous phase was extracted with DCM (3×). The organic phases were dried(MgSO₄), filtered and concentrated to afford the title compound (190 mg,60%) as a dark brown oil. ¹H NMR (500 MHz, CDCl₃) δ 5.25-5.10 (m, 1H),3.64 (t, J=5.4 Hz, 2H), 2.97-2.86 (m, 2H), 2.80 (ddd, J=30.4, 11.6, 5.0Hz, 1H), 2.70 (dd, J=6.1, 4.8 Hz, 2H), 2.55-2.48 (m, 1H), 2.22-1.99 (m,2H). HRMS (ESI⁺): calcd for C₆H₁₃FNO (M+H)⁺, 134.0976; found 134.0974.

Preparation of Compound 76,(S)-6-bromo-2-(2-(3-fluoropyrrolidin-1-yl)ethoxy)quinoline

This was prepared as for Compound 3, substituting Compound 75 for(R)-(−)-1-methyl-3-hydroxypyrrolidine. The crude material was purifiedby silica gel column chromatography using a gradient of 1 to 2% MeOH inDCM to afford the title compound as a pale yellow solid. ¹H NMR (500MHz, CDCl₃) δ 7.88 (d, J=8.8 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.72-7.64(m, 2H), 6.95 (d, J=8.9 Hz, 1H), 5.19 (dddt, J=55.6, 6.6, 5.0, 1.8 Hz,1H), 4.66-4.57 (m, 2H), 3.04-2.87 (m, 5H), 2.67-2.60 (m, 1H), 2.25-2.01(m, 2H). HRMS (ESI⁺): calcd for C₁₅H₁₇ ⁷⁹BrFN₂O (M+H)⁺, 339.0503; found339.0500.

Preparation of Compound 77,(S)-2-(2-(3-fluoropyrrolidin-1-yl)ethoxy)quinoline-6-carboxylic acidhydrochloride

This was prepared as for Compound 4, substituting Compound 76 forCompound 3 to afford the title compound as a pale yellow solid. ¹H NMR(500 MHz, DMSO) δ 13.12 (br s, 1H), 11.79 (br s, 0.5H), 11.44 (br s,0.5H), 8.59 (s, 1H), 8.49-8.46 (m, 1H), 8.18-8.14 (m, 1H), 7.85 (d,J=8.7 Hz, 1H), 7.21-7.16 (m, 1H), 5.56-5.36 (m, 1H), 4.88-4.74 (m, 2H),4.04-3.85 (m, 1H), 3.83-3.65 (m, 3H), 3.62-3.35 (m, 2H), 2.40-2.06 (m,2H). HRMS (ESI⁺): calcd for C₁₆H₁₈FN₂O₃(M+H)⁺, 305.1296; found 305.1296.

Preparation of Compound 78,4-(2-((6-bromoquinolin-2-yl)oxy)ethyl)morpholine

This was prepared as for Compound 3, substituting4-(2-hydroxyethyl)morpholine for (R)-(−)-1-methyl-3-hydroxypyrrolidine.The product precipitated as a pale pink solid after the addition ofwater, and was isolated by filtration and used in the next step withoutfurther purification. ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J=8.9 Hz, 1H),7.86 (s, 1H), 7.68 (s, 2H), 6.94 (d, J=8.9 Hz, 1H), 4.61 (t, J=5.8 Hz,2H), 3.77-3.71 (m, 4H), 2.84 (t, J=5.8 Hz, 2H), 2.65-2.55 (m, 4H). HRMS(ESI⁺): calcd for C₁₅H₁₈ ⁷⁹BrN₂O₂(M+H)⁺, 337.0546; found 337.0544.

Preparation of Compound 79, 2-(2-morpholinoethoxy)quinoline-6-carboxylicacid hydrochloride

This was prepared as for Compound 4, substituting Compound 78 forCompound 3 to afford the title compound as a pale yellow solid. ¹H NMR(500 MHz, DMSO) δ 11.87 (br s, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.47 (d,J=8.9 Hz, 1H), 8.16 (dd, J=8.7, 2.0 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H),7.16 (d, J=8.9 Hz, 1H), 4.91-4.85 (m, 2H), 3.99-3.85 (m, 4H), 3.66-3.59(m, 4H), 3.56-3.48 (m, 2H), 3.25-3.17 (m, 2H). HRMS (ESI⁺): calcd forC₁₆H₁₉N₂O₄ (M+H)⁺, 303.1339; found 303.1340.

Preparation of Compound 80, methyl2-(pyrrolidin-1-ylmethyl)quinoline-6-carboxylate

Pyrrolidine (0.144 mL, 1.74 mmol) was added to a solution of Compound 13(0.25 g, 1.16 mmol) in dry DCM (5.0 mL). The reaction mixture wasstirred at rt for 6 hrs, before NaBH(OAc)₃ (0.369 g, 1.74 mmol) wasadded and the reaction mixture was stirred overnight at rt, diluted withDCM, washed with saturated NaHCO₃(aq) (1×). The aqueous phase wasextracted with DCM (1×). The organic phase was dried (MgSO₄), filteredand concentrated. The crude material was purified by silica gel columnchromatography using a gradient of 2 to 5% MeOH in DCM to afford thetitle compound (225 mg, 72% as a brown solid. ¹H NMR (500 MHz, CDCl₃) δ8.58 (d, J=1.9 Hz, 1H), 8.32-8.24 (m, 2H), 8.10 (d, J=8.8 Hz, 1H), 7.85(v br s, 1H), 4.14 (br s, 2H), 4.00 (s, 3H), 2.83 (v br s, 4H), 1.94 (brs, 4H). HRMS (ESI⁺): calcd for C₁₆H₁₉N₂O₂ (M+H)⁺, 271.1441; found271.1444.

Preparation of Compound 81,2-(pyrrolidin-1-ylmethyl)quinoline-6-carboxylic acid hydrochloride

NaOH (1.018 M, 2.29 mL, 2.33 mmol) was added to a solution of Compound80 (0.210 g, 0.777 mmol) in THF (3.0 mL), followed by MeOH (1.0 mL) andthe reaction mixture was stirred at rt overnight, and then heated to 35°C. for 23 hrs, cooled, concentrated to remove THF and MeOH. Theremaining aqueous phase was washed with EtOAc (1×), acidified to pH 3with 2 M HCl. A ppt formed, which was filtered off and discarded. TheFiltrate was then concentrated to dryness to afford the title compoundas a brown solid. HRMS (ESI⁺): calcd for C₁₅H₁₇N₂O₂ (M+H)⁺, 257.1284;found 257.1284.

Preparation of Compound 82, methyl 4-methoxyquinoline-6-carboxylate

Sodium methoxide (0.195 g, 3.61 mmol) was added to a suspension ofCompound 57 (0.200 g, 0.902 mmol) in dry MeOH (5.0 mL). The reactionmixture was heated at reflux for 19 h, cooled to rt, and then 4 M HCl indioxane (2.26 mL, 9.02 mmol) was added and the reaction mixture washeated to 70° C. for 6 h, cooled, concentrated, diluted with EtOAc, andwashed with saturated NaHCO₃(aq) (1×). The aqueous phase was extractedwith EtOAc (1×). The organic phases were washed with brine (1×), dried(MgSO₄), filtered and concentrated to afford the title compound (186 mg,95%) as an off-white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.97 (d, J=1.9 Hz,1H), 8.83 (br d, J=5.3 Hz, 1H), 8.28 (dd, J=8.8, 2.0 Hz, 1H), 8.07 (d,J=8.8 Hz, 1H), 6.80 (d, J=5.3 Hz, 1H), 4.09 (s, 3H), 3.99 (s, 3H). HRMS(ESI⁺): calcd for C₁₂H₁₂NO₃ (M+H)⁺, 218.0812; found 218.0818.

Preparation of Compound 83, 4-methoxyquinoline-6-carboxylic acidhydrochloride

LiOH (0.97 M, 1.424 mL, 1.381 mmol) was added to a solution of Compound82 (0.050 g, 0.23 mmol) in THF (2.0 mL) and MeOH (0.40 mL) and thereaction mixture was stirred at rt overnight, concentrated to removeorganic solvents, diluted with water, and washed with EtOAc (1×). Theaqueous phase was acidified to ˜pH 2 with 2 M HCl, then concentrated todryness to afford the title compound as a pale brown hygroscopic solid.¹H NMR (500 MHz, DMSO) δ 9.20 (d, J=6.4 Hz, 1H), 8.85 (d, J=1.9 Hz, 1H),8.46 (dd, J=8.8, 1.9 Hz, 1H), 8.37 (d, J=8.9 Hz, 1H), 7.54 (d, J=6.3 Hz,1H), 4.30 (s, 3H). HRMS (ESI⁺): calcd for C₁₁H₁₀NO₃ (M+H)⁺, 204.0655;found 204.0658.

Preparation of Compound 84, 2-(pyrrolidin-1-yl)propan-1-ol

A mixture of DL-alaninol (0.500 g, 6.66 mmol), 1,4-dibromobutane (1.51g, 6.99 mmol), sodium bicarbonate (1.23 g, 14.6 mmol), and 3 Å molecularsieves (powdered) in dry toluene (5.4 mL) was heated to reflux for 22.5h, cooled to rt, and filtered to remove solids. The filtrate wasconcentrated, re-dissolved in DCM, washed with 1 M NaOH (1×). Theaqueous phase was extracted with DCM (2×). The combined organic phaseswere dried (MgSO₄), filtered and concentrated. This impure material wasdissolved in 0.5 M HCl, and washed with DCM (1×). The aqueous phase wasmade basic (pH>12) with 1 M NaOH, then extracted w/DCM (6×). This latterorganic phase was dried (MgSO₄), filtered and concentrated to afford thetitle compound (417 mg, 48%) as a pale yellow oil. ¹H NMR (500 MHz,CDCl₃) δ 3.60 (dd, J=10.4, 4.5 Hz, 1H), 3.36 (dd, J=10.4, 6.3 Hz, 1H),2.92 (br s, 1H), 2.73-2.65 (m, 1H), 2.61-2.56 (m, 4H), 1.81-1.72 (m,4H), 1.04 (d, J=6.6 Hz, 3H). HRMS (ESI⁺): calcd for C₇H₁₆NO (M+H)⁺,130.1226; found 130.1228.

Preparation of Compound 85,6-bromo-2-(2-(pyrrolidin-1-yl)propoxy)quinoline

This was prepared as for Compound 3, substituting Compound 84 for(R)-(−)-1-methyl-3-hydroxypyrrolidine. The crude material was purifiedby silica gel column chromatography using a gradient of 3 to 15% MeOH inDCM to afford the title compound as a pale yellow solid. ¹H NMR (500MHz, CDCl₃) δ 7.88 (d, J=8.9 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.70-7.65(m, 2H), 6.97 (d, J=8.9 Hz, 1H), 4.61 (dd, J=11.0, 4.3 Hz, 1H), 4.41(dd, J=11.0, 5.6 Hz, 1H), 2.81-2.66 (m, 5H), 1.84-1.79 (m, 4H), 1.30 (d,J=6.5 Hz, 3H). HRMS (ESI⁺): calcd for C₁₆H₂₀ ⁷⁹BrN₂O (M+H)⁺, 335.0754;found 335.0750.

Preparation of Compound 86,2-(2-(pyrrolidin-1-yl)propoxy)quinoline-6-carboxylic acid hydrochloride

This was prepared as for Compound 4, substituting Compound 85 forCompound 3 to afford the title compound as a pale yellow solid. ¹H NMR(500 MHz, DMSO) δ 13.12 (v br s, 1H), 11.32 (br s, 1H), 8.59 (d, J=1.8Hz, 1H), 8.48 (d, J=8.9 Hz, 1H), 8.16 (dd, J=8.8, 2.0 Hz, 1H), 7.85 (d,J=8.7 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 4.79-4.67 (m, 2H), 3.85-3.77 (m,1H), 3.61-3.48 (m, 2H), 3.25-3.15 (m, 2H), 2.04-1.83 (m, 4H), 1.46 (d,J=6.7 Hz, 3H). HRMS (ESI⁺): calcd for C₁₇H₂₁N₂O₃ (M+H)⁺, 301.1547; found301.1546.

Preparation of Compound 87, ethyl2-(2-(dimethylamino)ethyl)quinoline-6-carboxylate

A solution of Me₂NH.HCl (0.190 g) and formaldehyde solution (37%, 0.175mL) was made. 68 uL of this was added to ethyl2-methylquinoline-6-carboxylate (0.200 g, 0.929 mmol), followed by aminimum amount of MeOH (<0.1 mL) in order to allow the mixture to stir.The reaction mixture was then heated to 50° C. for 110 min, and then atrt for 2 h, diluted with water, and washed with diethyl ether (2×). Theaqueous phase was made basic with 1 M NaOH, then extracted with EtOAc(2×). This organic phase was washed with brine (1×), dried (Na₂SO₄),filtered and concentrated. The crude material was purified by silica gelcolumn chromatography using a gradient of 1 to 4.5% MeOH in DCMcontaining 1% 2 M NH₃ in MeOH to afford the title compound (39 mg, 31%)as a very pale yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 8.55 (d, J=1.8 Hz,1H), 8.28 (dd, J=8.8, 1.9 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 8.06 (d,J=8.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 4.45 (q, J=7.1 Hz, 2H), 3.22-3.15(m, 2H), 2.88-2.80 (m, 2H), 2.35 (s, 6H), 1.45 (t, J=7.1 Hz, 2H). HRMS(ESI⁺): calcd for C₁₆H₂₁N₂O₂ (M+H)⁺, 273.1598; found 273.1597.

Preparation of Compound 88,2-(2-(dimethylamino)ethyl)quinoline-6-carboxylic acid hydrochloride

LiOH (1.984 M, 0.108 mL, 0.215 mmol) was added to a solution of Compound87 (0.039 g, 0.14 mmol) in THF (2.0 mL) and MeOH (1.0 mL) and thereaction mixture was stirred at rt for 24 hrs. Additional LiOH (1.984 M,0.108 mL, 0.215 mmol) was added and the reaction mixture stirred at rtfor 24 h, then water (1 mL) was added and the reaction mixture wasstirred for a further 24 h. NaOH (3.0 M, 0.048 mL) was added and thereaction mixture stirred at rt for 24 h before additional NaOH (3.0 M,0.010 mL) was added, and the reaction mixture was stirred at rt for 5.5h, concentrated to remove organic solvent, diluted with water, washedwith EtOAc (1×). The aqueous phase was acidified to pH 3 with 2 M HCl,then concentrated to afford the title compound as a paly yellow solid(contains LiCl and NaCl) and was used without further purification. HRMS(ESI⁺): calcd for C₁₄H₁₇N₂O₂ (M+H)⁺, 245.1284; found 245.1282.

Preparation of Compound 89, 6-(ethoxycarbonyl)-2-methylquinoline 1-oxide

3-Chloroperbenzoic acid (0.695 g, 3.02 mmol) was added to a solution ofethyl 2-methylquinoline-6-carboxylate (0.500 g, 2.323 mmol) in dry DCM(7 mL) at 0° C. The r×n mix was then allowed to warm to rt, stirredovernight, washed with 10% sodium sulfite (1×), saturated NaHCO₃ (1×),brine (1×), dried (MgSO4), filtered and concentrated. The crude materialwas purified by silica gel column chromatography using a gradient of 80to 100% EtOAc in PE, and then from 0 to 10% MeOH in EtOAc to afford thetitle compound (463 mg, 86%) as a pale yellow solid. ¹H NMR (500 MHz,CDCl₃) δ 8.82 (d, J=9.1 Hz, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.33 (dd,J=9.1, 1.8 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 4.46(q, J=7.1 Hz, 2H), 2.74 (s, 3H), 1.45 (t, J=7.1 Hz, 3H). HRMS (ESI⁺):calcd for C₁₃H₁₄NO₃ (M+H)⁺, 232.0976; found 232.0976.

Preparation of Compound 90, ethyl2-((tosyloxy)methyl)quinoline-6-carboxylate

To a solution of Compound 89 (0.274 g, 1.18 mmol) in dry acetonitrile(10 mL) at 0° C. was added K₂CO₃ (0.246 g, 1.78 mmol) followed byp-toluenesulfonyl chloride (0.271 g, 1.42 mmol). The reaction mixturewas stirred at 0° C. for 5 hr 45 min, diluted with saturated NaHCO₃,extracted with EtOAc (2×). The organic phase was washed with water (1×),brine (1×), dried (MgSO₄), filtered and concentrated. The crude materialwas purified by silica gel column chromatography using a gradient of 14to 28% EtOAc in PE to afford the title compound (186 mg, 41%) as anorange solid. ¹H NMR (500 MHz, CDCl₃) δ 8.58 (d, J=1.9 Hz, 1H),8.34-8.25 (m, 2H), 8.01 (d, J=8.8 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.63(d, J=8.5 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 5.32 (s, 2H), 4.45 (q, J=7.1Hz, 2H), 2.42 (s, 3H), 1.45 (t, J=7.1 Hz, 3H). HRMS (ESI⁺): calcd forC₂₁H₂₀NO₅S (M+H)⁺, 386.1057; found 386.1071.

Preparation of Compound 91, ethyl2-((4-methylpiperazin-1-yl)methyl)quinoline-6-carboxylate

1-Methylpiperazine (0.058 mL, 0.52 mmol) was added to a solution ofCompound 90 (0.080 g, 0.21 mmol) in dry THF (1.5 mL). The reactionmixture was heated at reflux for 1 h 45 min, then at rt for 2 h,concentrated, added EtOAc, washed with water (1×), NaHCO₃ (1×). Theaqueous phase was extracted with EtOAc (1×) and the combined organicphases were dried (MgSO₄), filtered and concentrated to afford the titlecompound (64 mg, 98%) as a pale yellow solid. ¹H NMR (500 MHz, CDCl₃) δ8.56 (d, J=1.9 Hz, 1H), 8.29 (dd, J=8.8, 1.9 Hz, 1H), 8.22 (d, J=8.5 Hz,1H), 8.09 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 4.45 (q, J=7.1 Hz,2H), 3.86 (s, 2H), 2.61 (br s, 4H), 2.49 (br s, 4H), 2.31 (s, 3H), 1.45(t, J=7.1 Hz, 3H). HRMS (ESI⁺): calcd for C₁₈H₂₄N₃O₂ (M+H)⁺, 314.1863;found 314.1871.

Preparation of Compound 92,2-((4-methylpiperazin-1-yl)methyl)quinoline-6-carboxylic aciddihydrochloride

NaOH (0.82 M, 0.735 mL, 0.60 mmol) was added to a solution of Compound91 (0.063 g, 0.20 mmol) in THF (1.0 mL). MeOH (0.25 mL) was then addedand the reaction mixture was stirred at rt overnight, concentrate toremove organic solvents, diluted with water, washed with EtOAc (1×). Theaqueous phase was acidified with 2 M HCl to pH 2-3, then concentrated todryness to afford the title compound (contains NaCl) as a light brownsolid. ¹H NMR (500 MHz, DMSO) δ 13.33 (v br s, 1H), 11.77 (br s, 1H),8.72 (d, J=1.9 Hz, 1H), 8.69 (d, J=8.5 Hz, 1H), 8.26 (dd, J=8.8, 1.9 Hz,1H), 8.16 (d, J=8.9 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 4.53 (br s, 2H),3.83-3.45 (br m, 8H), 2.80 (s, 3H). HRMS (ESI⁺): calcd for C₁₆H₂₀N₃O₂(M+H)⁺, 286.1550; found 286.1553.

Preparation of Compound 93, methyl 6-(thiazol-4-ylmethoxy)nicotinate

4-(Hydroxymethyl)-1,3-thiazole (0.187 mL, 2.17 mmol) was added to asuspension of NaH (60%, 0.054 g, 2.3 mmol) in dry THF (6 mL) at 0° C.After a few minutes, the reaction mixture was allowed to warm to rt,stirred for 20 min before methyl 6-chloropyridine-3-carboxylate (0.339g, 1.97 mmol) was added and the reaction mixture was heated at refluxfor 4.5 h, cooled, concentrated, added water and saturated NaHCO₃. Themixture was extracted with DCM (3×). The organic phase was dried(Na₂SO₄), filtered and concentrated. The crude material was purified bysilica gel column chromatography using a gradient of 20 to 25% EtOAc inPE to afford the title compound (106 mg, 22%) as a white solid. ¹H NMR(500 MHz, CDCl₃) δ 8.87-8.84 (m, 2H), 8.18 (dd, J=8.7, 2.4 Hz, 1H), 7.43(dd, J=1.9, 0.9 Hz, 1H), 6.86 (dd, J=8.5, 0.8 Hz, 1H), 5.64 (d, J=0.7Hz, 2H), 3.91 (s, 3H). HRMS (ESI⁺): calcd for C₁₁H₁₁N₂O₃S (M+H)⁺,251.0485; found 251.0487.

Preparation of Compound 94, 6-(thiazol-4-ylmethoxy)nicotinic acid

LiOH (1.42 M, 0.580 mL, 0.823 mmol) was added to a solution of Compound93 (0.103 g, 0.412 mmol) in THF (2.5 mL), followed by MeOH (0.8 mL). Thereaction mixture was stirred at rt overnight, concentrated to removeorganic solvents, diluted with water, washed with EtOAc (1×). Theaqueous phase was acidified to pH 2-3 with 2 M HCl and the resultingprecipitate was isolated by filtration, washed with water to afford thetitle compound (85 mg, 87%) as a white solid. ¹H NMR (500 MHz, DMSO) δ13.08 (br s, 1H), 9.12 (d, J=1.9 Hz, 1H), 8.74 (d, J=2.5 Hz, 1H), 8.17(dd, J=8.7, 2.4 Hz, 1H), 7.81-7.77 (m, 1H), 6.97 (dd, J=8.8, 0.6 Hz,1H), 5.53 (s, 2H). HRMS (ESI⁺): calcd for C₁₀H₉N₂O₃S (M+H)⁺, 237.0328;found 237.0329.

Preparation of Compound 95, ethyl2-((dimethylamino)methyl)quinoline-6-carboxylate

A solution of Compound 90 (0.062 g, 0.16 mmol) in dimethylamine (2.0 Min THF, 1 mL, 2.0 mmol) was heated in a microwave at 60° C. for 1 h,cooled, concentrated, diluted with EtOAc, washed with water (1×), NaHCO₃(1×). The aqueous phase was extracted with EtOAc (1×). The combinedorganic phases were dried (Na₂SO₄), filtered and concentrated to affordthe title compound (42 mg, 100%) as an orange oil. ¹H NMR (500 MHz,CDCl₃) δ 8.57 (d, J=1.8 Hz, 1H), 8.29 (dd, J=8.8, 1.9 Hz, 1H), 8.23 (d,J=8.5 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 4.45 (q,J=7.2 Hz, 2H), 3.79 (s, 2H), 2.35 (s, 6H), 1.45 (t, J=7.1 Hz, 3H).

Preparation of Compound 96,2-((dimethylamino)methyl)quinoline-6-carboxylic acid hydrochloride

NaOH (1.04 M, 0.304 mL, 0.317 mmol) was added to a solution of Compound95 (0.041 g, 0.16 mmol) in THF (1 mL) and MeOH (0.3 mL). The reactionmixture was stirred at rt overnight, and then water (0.5 mL) and NaOH(1.15 M, 0.276 mL, 0.317 mmol) was added and the reaction mixturestirred at rt for 48 h, concentrated to remove organic solvents, dilutedwith water, washed with EtOAc (1×). The aqueous phase was acidified topH 3 with 2 M and then concentrated to dryness to afford the titlecompound (contains NaCl) as a pale yellow solid. ¹H NMR (500 MHz, DMSO)δ 8.70 (d, J=1.8 Hz, 1H), 8.65 (d, J=8.5 Hz, 1H), 8.25 (dd, J=8.8, 1.9Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 4.42 (br s,2H), 2.70 (s, 6H).

Preparation of Compound 97, 2-(4,4-difluoropiperidin-1-yl)ethanol

2-Bromoethanol (0.164 mL, 2.31 mmol) was added to a suspension of4,4-difluoropiperidine hydrochloride (0.354 g, 2.25 mmol) and potassiumcarbonate (0.683 g, 4.94 mmol) in dry acetonitrile (5 mL) and thereaction mixture was as heated at reflux overnight, cooled to rt,filtered, and the filtrate concentrated. Added diethyl ether, extractedwith 1 M HCl (2×). The aqueous phase was made basic (pH>12) with solidNaOH, then extracted with DCM (3×). This organic phase was dried overK₂CO₃, filtered and concentrated to afford the title compound (216 mg,58%) as a colourless oil. ¹H NMR (500 MHz, CDCl₃) δ 3.79 (br t, J=4.7Hz, 2H), 2.92 (br s, 4H), 2.82 (br s, 2H), 2.23 (br s, 4H). HRMS (ESI⁺):calcd for C₇H₄F₂NO (M+H)⁺, 166.1038; found 166.1041.

Preparation of Compound 98,6-bromo-2-(2-(4,4-difluoropiperidin-1-yl)ethoxy)quinoline

This was prepared as for Compound 3, substituting Compound 97 for(R)-(−)-1-methyl-3-hydroxypyrrolidine. The crude material was purifiedby silica gel column chromatography using a gradient of 5 to 9% MeOH inDCM to afford the title compound as an off-white solid. ¹H NMR (500 MHz,CDCl₃) δ 7.91 (d, J=9.1 Hz, 1H), 7.87 (s, 1H), 7.71-7.66 (m, 2H), 6.94(d, J=8.9 Hz, 1H), 4.63 (br s, 2H), 2.91 (br s, 2H), 2.73 (br s, 4H),2.04 (br s, 4H). HRMS (ESI⁺): calcd for C₁₆H₁₈ ⁷⁹BrF₂N₂O (M+H)⁺,371.0565; found 371.0563.

Preparation of Compound 99,2-(2-(4,4-difluoropiperidin-1-yl)ethoxy)quinoline-6-carboxylic acidhydrochloride

This was prepared as for Compound 4, substituting Compound 98 forCompound 3 to afford the title compound as a white solid. ¹H NMR (500MHz, DMSO) δ 13.09 (br s, 1H), 11.93, (br s, 1H), 8.57 (d, J=2.0 Hz,1H), 8.44 (d, J=8.9 Hz, 1H), 8.14 (dd, J=8.7, 2.0 Hz, 1H), 7.83 (d,J=8.7 Hz, 1H), 7.13 (d, J=8.9 Hz, 1H), 4.71 (br s, 2H), 3.63 (br s, 2H),2.78 (br s, 4H), 2.10 (br s, 4H). HRMS (ESI⁺): calcd forC₁₇H₁₉F₂N₂O₃(M+H)⁺, 337.1358; found 337.1356.

Preparation of Compound 100,⁹ 1-(pyrrolidin-1-yl)propan-2-ol

Pyrrolidine (0.517 mL, 6.20 mmol) was added to a solution of propyleneoxide (0.361 mL, 5.17 mmol) in water (2.0 mL) at 0° C. The reactionmixture was stirred at this temp for a couple of minutes, then allowedto warm to rt, stirred overnight, diluted with a bit of water, extractedwith EtOAc (2×). The organic phase was dried (Na₂SO₄), filtered andconcentrated to afford the title compound (478 mg, 72%) as a colourlessoil. H NMR (500 MHz, CDCl₃) δ 3.83-3.75 (m, 1H), 2.70-2.65 (m, 2H), 2.53(dd, J=11.9, 10.5 Hz, 1H), 2.48-2.42 (m, 2H), 2.24 (dd, J=12.0, 2.9 Hz,1H), 1.80-1.73 (m, 4H), 1.13 (d, J=6.2 Hz, 3H).

Preparation of Compound 101,6-bromo-2-((1-(pyrrolidin-1-yl)propan-2-yl)oxy)quinoline

This was prepared as for Compound 3, substituting Compound 100 for(R)-(−)-1-methyl-3-hydroxypyrrolidine. The crude material was purifiedby silica gel column chromatography using a gradient of 3 to 13% MeOH inDCM to afford the title compound as a pale yellow oil. ¹H NMR (500 MHz,CDCl₃) δ 7.86 (d, J=8.9 Hz, 1H), 7.85-7.82 (m, 1H), 7.68-7.62 (m, 2H),6.89 (d, J=8.9 Hz, 1H), 5.67-5.60 (m, 1H), 2.85 (dd, J=12.6, 7.0 Hz,1H), 2.67 (dd, J=12.6, 5.0 Hz, 1H), 2.65-2.57 (m, 4H), 1.78-1.72 (m,4H), 1.41 (d, J=6.2 Hz, 3H). HRMS (ESI⁺): calcd for C₁₆H₂₀ ⁷⁹BrN₂O(M+H)⁺, 335.0754; found 335.0752.

Preparation of Compound 102,2-((1-(pyrrolidin-1-yl)propan-2-yl)oxy)quinoline-6-carboxylic acidhydrochloride

This was prepared as for Compound 4, substituting Compound 101 forCompound 3 to afford the title compound as a pale yellow solid. ¹H NMR(500 MHz, DMSO) δ 10.70 (s, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.46 (d, J=9.0Hz, 1H), 8.15 (dd, J=8.9, 2.1 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.14 (d,J=8.8 Hz, 1H), 5.79-5.72 (m, 1H), 3.60-3.48 (m, 4H), 3.15 (br s, 2H),1.97 (br s, 2H), 1.89 (br s, 2H), 1.44 (d, J=6.2 Hz, 3H). HRMS (ESI⁺):calcd for C₁₇H₂₁N₂O₃ (M+H)⁺, 301.1547; found 301.1543.

Example 89—Preparation of2-(2-aminoethoxy)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide

Trifluoroacetic acid (0.75 mL) was added to a solution of Example 21(0.039 g, 0.065 mmol) in dry DCM (0.75 mL) and the reaction mixture wasstirred at rt for 75 min, concentrated, added DCM and concentratedagain. Diluted with a small amount of MeOH, then slowly added halfsaturated NaHCO₃. The resulting precipitate was isolated by filtration,washed with water. The crude material was purified by silica gel columnchromatography using 10% MeOH in DCM then a gradient of 5 to 9% 2 MNH₃/MeOH to afford the title compound (22 mg, 68%) as an off-whitesolid. ¹H NMR (500 MHz, DMSO) δ 10.07 (s, 2H), 8.57 (d, J=2.0 Hz, 1H),8.39 (d, J=8.9 Hz, 1H), 8.22 (dd, J=8.7, 2.1 Hz, 1H), 7.89-7.84 (m, 2H),7.58 (dd, J=8.3, 2.2 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.51 (dd, J=8.5,2.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.7 Hz, 1H), 6.98 (d,J=8.4 Hz, 1H), 4.42 (t, J=5.8 Hz, 2H), 4.33-4.28 (m, 4H), 2.99 (t, J=5.9Hz, 2H), 2.24 (s, 3H). LRMS (ESI⁺): 499.26

Preparation of Compound 103, methyl 4-(pyridin-2-ylmethoxy)benzoate

A mixture of methyl 4-hydroxybenzoate (0.200 g, 1.315 mmol),2-(bromomethyl)pyridine hydrobromide (0.366 g, 1.45 mmol), and potassiumcarbonate (0.545 g, 3.94 mmol) in dry DMF (5.0 mL) was gradually heatedto 60° C. for 2.5 h, cooled to rt, diluted with water and the resultingprecipitate was isolated by filtration, washed with water and dried toafford the title compound (299 mg, 94%) as an off-white solid. ¹H NMR(500 MHz, CDCl₃) δ 8.61 (ddd, J=4.7, 1.7, 0.9 Hz, 1H), 8.00 (d, J=8.9Hz, 2H), 7.74 (td, J=7.8, 1.8 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.28-7.24(m, 1H), 7.01 (d, J=8.9 Hz, 2H), 5.27 (s, 2H), 3.88 (s, 3H). HRMS(ESI⁺): calcd for C₁₄H₁₃NO₃ (M+H)⁺, 244.0968; found 244.0965.

Preparation of Compound 104, 4-(pyridin-2-ylmethoxy)benzoic acid

LiOH (1.345 M, 1.803 mL, 2.425 mmol) was added to a solution of Compound103 (0.295 g, 1.21 mmol) in THF (6.0 mL), followed by MeOH (3.0 mL) andthe reaction mixture was stirred at rt for 3 days, concentrated toremove organic solvents, washed with EtOAc (1×). The aqueous phase wasacidified with 2 M HCl to pH 3 and the resulting precipitate wasisolated by filtration, washed with water and dried to afford the titlecompound (244 mg, 88%) as a white solid. ¹H NMR (500 MHz, DMSO) δ 12.66(br s, 1H), 8.59 (ddd, J=4.8, 1.7, 0.9 Hz, 1H), 7.89 (d, J=8.8 Hz, 2H),7.84 (td, J=7.7, 1.7 Hz, 1H), 7.52 (br d, J=7.8 Hz, 2H), 7.36 (ddd,J=7.7, 4.8, 1.1 Hz, 1H), 7.11 (d, J=8.8 Hz, 2H), 5.26 (s, 2H). HRMS(ESI⁺): calcd for C₁₃H₁₂NO₃ (M+H)⁺, 230.0812; found 230.0811.

Preparation of Compound 105, methyl 4-(thiazol-5-ylmethoxy)benzoate

Diisopropyl azodicarboxylate (0.531 mL, 2.56 mmol) was added dropwise toa solution of methyl 4-hydroxybenzoate (0.300 g, 1.97 mmol),5-(hydroxymethyl)-1,3-thiazole (0.172 mL, 1.97 mmol), andtriphenylphosphine (0.672 g, 2.56 mmol) in dry THF (5.5 mL) at 0° C. Thereaction mixture was then allowed to warm to rt, stirred overnightconcentrated, diluted with EtOAc, washed with 1 M NaOH (1×), brine (1×),dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by silica gel column chromatography using a gradient of 28 to40% EtOAc in PE to afford the title compound (436 mg, 89%) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ 8.88 (s, 1H), 8.02 (d, J=8.8 Hz, 2H),7.95-7.94 (m, 1H), 6.99 (d, J=8.8 Hz, 2H), 5.35 (d, J=1.1 Hz, 2H), 3.89(s, 3H). HRMS (ESI⁺): calcd for C₁₂H₁₂NO₃S (M+H)⁺, 250.0532; found250.0533.

Preparation of Compound 106, 4-(thiazol-5-ylmethoxy)benzoic acid

LiOH (1.345 M, 2.51 mL, 3.38 mmol) was added to a solution of Compound105 (0.421 g, 1.69 mmol) in THF (8.0 mL), followed by MeOH (2.5 mL) andthe reaction mixture was stirred at rt for 22 h, concentrated to removeorganic solvents, diluted with a bit of water, and washed with EtOAc(1×). The aqueous phase was acidified to pH 2 with 2 M HCl and theresulting precipitate was isolated by filtration, washed with water anddried to afford the title compound (335 mg, 84%) as a white solid. ¹HNMR (500 MHz, DMSO) δ 12.68 (s, 1H), 9.13 (s, 1H), 8.04 (s, 1H), 7.90(d, J=8.8 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 5.48 (s, 2H). HRMS (ESI⁺):calcd for C₁₁H₁₀NO₃S (M+H)⁺, 236.0376; found 236.0375.

Preparation of Compound 107, methyl2-chloro-4-methoxyquinoline-6-carboxylate

mCPBA (0.185 g, 0.802 mmol) was added to a solution of Compound 82(0.134 g, 0.617 mmol) in dry DCM (2.0 mL) at 0° C. The reaction mixturewas then warmed to rt and stirred for 20 h diluted with DCM, washed with10% sodium sulfite (1×). The aqueous phase was extracted with DCM (1×).The organic phases were washed with NaHCO₃ (1×), brine (1×), dried(MgSO₄), filtered and concentrated to afford the4-methoxy-6-(methoxycarbonyl)quinoline 1-oxide intermediate as a yellowsolid. The N-oxide intermediate was dissolved in dry DCM (2.0 mL), andto this was added phosphorus oxychloride (0.765 mL, 8.20 mmol) slowlywhile cooling flask in a water bath (exotherm). The reaction mixture wasthen heated to 50° C. for 17 h, and then at 55° C. for 6 h beforeadditional POCl₃ (0.29 mL, 3.1 mmol) was added and the reaction mixturewas heated to 50° C. for 18 h, cooled to rt, diluted with EtOAc, washedwith NaHCO₃ (3×). The aqueous phase was made basic with 1 M NaOH, thenextracted with EtOAc (1×). The combined organic phases were washed withbrine (1×), dried (MgSO₄), filtered and concentrated. The crude materialwas purified by silica gel column chromatography using a gradient of 11to 17% EtOAc in PE to afford the title compound (99 mg, 64%) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ 8.89 (d, J=1.6 Hz, 1H), 8.30 (dd,J=8.8, 2.0 Hz, 1H), 7.96 (dd, J=8.8, 0.6 Hz, 1H), 6.80 (s, 1H), 4.10 (s,3H), 3.99 (s, 3H). HRMS (ESI⁺): calcd for C₁₂H₁₁ ³⁵ClNO₃ (M+H)⁺,252.0422; found 252.0428.

Preparation of Compound 108,4-methoxy-2-(2-methoxyethoxy)quinoline-6-carboxylic acid

NaH (60% in mineral oil, 0.014 g, 0.60 mmol) was added to2-methoxyethanol (0.75 ml, 9.5 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for a few minutes, then at rt for 20-25 min beforeCompound 107 (0.050 g, 0.20 mmol) was added. The resulting suspensionwas then heated to 70° C. for 24 h, cooled to rt, diluted with water,acidified to pH 3 with 2 M HCl. The resulting solid was isolated byfiltration, washed with water and dried. The crude material was purifiedby silica gel column chromatography using a gradient of 2 to 5% MeOH inDCM to afford the title compound (16 mg, 29%) as a white solid. ¹H NMR(500 MHz, CDCl₃) δ 8.88 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.8, 2.1 Hz, 1H),7.78 (d, J=8.7 Hz, 1H), 6.36 (s, 1H), 4.70-4.64 (m, 2H), 4.02 (s, 3H),3.83-3.78 (m, 2H), 3.47 (s, 3H). HRMS (ESI⁺): calcd for C₁₄H₁₆NO₅(M+H)⁺,278.1023; found 278.1024.

Preparation of Compound 109, 6-carboxyquinoline 1-oxide

NaOH (0.92 M, 1.605 mL, 1.48 mmol) was added to a solution of6-(methoxycarbonyl)quinoline 1-oxide (0.1 g, 0.492 mmol, synthesised asdescribed for Compounds 56 and 57) in THF (3 mL), followed by MeOH (0.5mL) and the reaction mixture was stirred overnight at rt, concentratedto remove organic solvents, diluted with water, washed with EtOAc (1×).The aqueous phase was acidified with 2 M HCl to pH 2-3, and theresulting solid was isolated by filtration, washed with water and driedto afford the title compound (79 mg, 85%) as an off-white solid. ¹H NMR(500 MHz, DMSO) δ 13.53 (br s, 1H), 8.75 (d, J=1.7 Hz, 1H), 8.68 (dd,J=6.2, 0.9 Hz, 1H), 8.60 (d, J=9.1 Hz, 1H), 8.24 (dd, J=9.1, 1.8 Hz,1H), 8.13 (d, J=8.5 Hz, 1H), 7.56 (dd, J=8.5, 6.1 Hz, 1H). HRMS (ESI⁺):calcd for C₁₀H₈NO₃ (M+H)⁺, 190.0499; found 190.0506.

Preparation of Compound 110, methyl 4-cyanoquinoline-6-carboxylate

A mixture of Compound 57 (0.200 g, 0.902 mmol), Zn(CN)₂ (0.212 g, 1.80mmol), and Pd(PPh₃)₄(0.104 g, 0.0900 mmol) in dry DMF (2.3 mL) washeated in a microwave reactor to 160° C. for 30 min, cooled to rt,diluted with EtOAc, filtered through celite, diluted further withtoluene, washed with water (2×), brine (1×), dried (MgSO₄), filtered andconcentrated. Added heptane and concentrated (2×) to remove residualDMF. The crude material was combined with the crude from a separatereaction (0.23 mmol scale) and purified by silica gel columnchromatography using a gradient of 22 to 25% EtOAc in PE to afford thetitle compound (213 mg, 89%) as an off-white solid. ¹H NMR (500 MHz,CDCl₃) δ 9.14 (d, J=4.2 Hz, 1H), 8.92 (d, J=1.9 Hz, 1H), 8.46 (dd,J=8.8, 1.8 Hz, 1H), 8.28 (d, J=8.7 Hz, 1H), 7.81 (d, J=4.3 Hz, 1H), 4.04(s, 3H). HRMS (ESI⁺): calcd for C₁₂H₉N₂O₂(M+H)⁺, 213.0658; found213.0663.

Preparation of Compound 111, 4-cyanoquinoline-6-carboxylic acid

A solution of LIOH (0.93 M), 2.05 ml, 1.91 mmol) was added to a solutionof Compound 110 (0.207 g, 0.975 mmol) in THF (7 mL), followed by MeOH (3mL) and the reaction mixture was stirred at rt overnight. AdditionalLiOH (0.769M, 2.7 ml, 2.1 mmol) was added and reaction mixture wasstirred at rt for 4 h, concentrated to remove organic solvents, andwashed with EtOAc (1×). The aqueous phase was acidified to pH 2-3 with 2M HCl, and the resulting precipitate was isolated by filtration, washedwith water and dried. The crude material was suspended in hot MeOH,cooled, and the solid isolated by filtration, and washed with MeOH anddried to afford the title compound, as a mixture with the amide fromnitrile hydrolysis. This mixture was used in the following step withoutfurther purification. HRMS (ESI⁺): calcd for C₁₁H₇N₂O₂(M+H)⁺, 199.0502;found 199.0502.

Preparation of Compound 112, methyl 6-(pyridin-2-ylmethoxy)nicotinate

2-(Hydroxymethyl)pyridine (0.169 mL, 1.75 mmol) was added to asuspension of NaH (60% in mineral oil, 0.044 g, 1.8 mmol) in dry THF(4.5 mL) at 0° C. After a few minutes, the reaction mixture was allowedto warm to rt, stirred for 20 min before methyl6-chloropyridine-3-carboxylate (0.250 g, 1.46 mmol) was added and thereaction mixture was heated at reflux for 4 h (shortly after heating, anadditional 3 mL of THF was added to help the thick reaction mixture tobe stirred efficiently). The reaction mixture was cooled to rt,concentrated, added water and saturated NaHCO₃ and the mixture wasextracted with DCM (3×). The organic phase was dried (Na₂SO₄), filteredand concentrated. The crude material was purified by silica gel columnchromatography using a gradient of 25 to 50% EtOAc in PE to afford thetitle compound (104 mg, 29%) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ8.83 (dd, J=2.5, 0.8 Hz, 1H), 8.62 (ddd, J=4.8, 1.8, 1.0 Hz, 1H), 8.19(dd, J=8.7, 2.4 Hz, 1H), 7.70 (td, J=7.7, 1.7 Hz, 1H), 7.44 (d, J=7.9Hz, 1H), 7.24 (ddd, J=7.6, 4.8, 0.8 Hz, 1H), 6.90 (dd, J=8.7, 0.6 Hz,1H), 5.58 (s, 2H), 3.91 (s, 3H). HRMS (ESI⁺): calcd for C₁₃H₁₃N₂O₃(M+H)⁺, 245.0921; found 245.0922.

Preparation of Compound 113, 6-(pyridin-2-ylmethoxy)nicotinic acid

LiOH (1.345 M, 0.615 mL, 0.827 mmol) was added to a solution of Compound112 (0.101 g, 0.414 mmol) in THF (2 mL), followed by MeOH (0.6 mL) andthe reaction mixture was stirred at rt for 26 h, concentrated to removeorganic solvents, diluted with water, and washed with EtOAc (1×). Theaqueous phase was acidified to pH 2-3 with 2 M HCl, and the resultingprecipitate was isolated by filtration, washed with water and dried toafford the title compound (79 mg, 83%) as a white solid. ¹H NMR (500MHz, DMSO) δ 13.07 (s, 1H), 8.71 (dd, J=2.5, 0.8 Hz, 1H), 8.56 (ddd,J=5.0, 1.8, 1.1 Hz, 1H), 8.19 (dd, J=8.6, 2.4 Hz, 1H), 7.81 (td, J=7.7,1.7 Hz, 1H), 7.46 (br d, J=7.8 Hz, 1H), 7.34 (ddd, J=7.6, 4.8, 1.1 Hz,1H), 7.04 (dd, J=8.6, 0.8 Hz, 1H), 5.50 (s, 2H). HRMS (ESI⁺): calcd forC₁₂H₁₁N₂O₃(M+H)⁺, 231.0764; found 231.0760.

Preparation of Compound 114, 6-bromo-2-(4-methylpiperazin-1-yl)quinoline

A solution of 6-bromo-2-chloroquinoline (0.200 g, 0.825 mmol) and1-methylpiperazine (0.459 mL, 4.12 mmol) in dry dioxane (4 mL) washeated at reflux for 19 h, cooled to rt, concentrated, diluted withEtOAc, washed with water (1×), brine (1×), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by silica gel columnchromatography using a gradient of 2 to 4% MeOH in DCM to afford thetitle compound (236 mg, 93%) as a pale yellow solid. ¹H NMR (500 MHz,CDCl₃) δ 7.79 (d, J=9.2 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.58 (dd,J=8.9, 2.1 Hz, 1H), 7.55 (d, J=8.9 Hz, 1H), 6.99 (d, J=9.2 Hz, 1H),3.79-3.73 (m, 4H), 2.58-2.51 (m, 4H), 2.36 (s, 3H). HRMS (ESI⁺): calcdfor C₁₄H₁₇ ⁷⁹BrN₃ (M+H)⁺, 306.0600; found 306.0587.

Preparation of Compound 115,2-(4-methylpiperazin-1-yl)quinoline-6-carboxylic acid hydrochloride

This was prepared as for Compound 4, substituting Compound 114 forCompound 3. After acidification of the aqueous phase this was loadedonto a flash-NH₂ column, eluted first with water, and then 1 M HCl. TheHCl fractions were concentrated to afford the title compound (13 mg, 9%)as a yellow-brown film. ¹H NMR (500 MHz, DMSO) δ 11.56 (br s, 1H), 8.43(d, J=2.1 Hz, 1H), 8.31 (br d, J=9.1 Hz, 1H), 8.09-8.02 (m, 1H), 7.68(br s, 1H), 7.42 (br d, J=9.2 Hz, 1H), 4.72 (br d, J=14.1 Hz, 2H), 3.16(s, 3H), 3.14-3.05 (m, 2H), 2.79-2.75 (m, 4H). HRMS (ESI⁺): calcd forC₁₅H₁₇N₃O₂ (M+H)⁺, 272.1394; found 272.1393.

Preparation of Compound 116, 4-(6-bromoquinolin-2-yl)morpholine

A solution of 6-bromo-2-chloroquinoline (0.200 g, 0.825 mmol) andmorpholine (0.719 mL, 8.25 mmol) in dry dioxane (3.5 mL) was heated atreflux overnight, cooled to rt, concentrated, diluted with EtOAc, washedwith water (2×), brine (1×), dried (Na₂SO₄), filtered and concentrated.The crude material was purified by a silica gel column chromatographyusing a gradient of 25 to 33% EtOAc in PE to afford the title compound(231 mg, 96%) as a pale orange solid. ¹H NMR (500 MHz, CDCl₃) δ 7.82 (d,J=9.1 Hz, 1H), 7.75 (d, J=2.1 Hz, 1H), 7.60 (dd, J=8.9, 2.1 Hz, 1H),7.57 (d, J=8.9 Hz, 1H), 6.97 (d, J=9.2 Hz, 1H), 3.88-3.82 (m, 4H),3.73-3.69 (m, 4H). HRMS (ESI⁺): calcd for C₁₃H₁₄ ⁷⁹BrN₂O (M+H)⁺,293.0284; found 293.0283.

Preparation of Compound 117, 2-morpholinoquinoline-6-carboxylic acid

This was prepared as for Compound 4, substituting Compound 116 forCompound 3. After acidification of the aqueous phase, it was extractedwith DCM (3×). The organic phases were dried (MgSO₄), filtered andconcentrated. The crude material was purified by silica gel columnchromatography using 1:1 PE:EtOAc+0.5% AcOH to afford the title compoundas a pale yellow solid. LRMS (ESI⁺): 259.21

Preparation of Compound 118, methyl 6-(methylcarbamoyl)nicotinate

A suspension of dimethyl 2,5-pyridinedicarboxylate (0.500 g, 2.56 mmol)and MgCl₂ (0.122 g, 1.28 mmol) in dry THF (10 mL) was stirred at rt for5 min, then methylamine (2.0 M in THF, 2.56 mL, 5.1 mmol) was addeddropwise over 10 min. The reaction mixture was stirred at rt for 3.5 h,after which time water (5 mL) and then 1 M HCl (2.6 mL) were added. ThepH was adjusted to 6 with 1 M NaOH, and the mixture extracted with EtOAc(3×). The organic phase was washed with brine (1×), dried (MgSO₄),filtered and concentrated to afford the title compound (485 mg, 97%) asa white solid. ¹H NMR (500 MHz, CDCl₃) δ 9.13 (dd, J=2.0, 0.8 Hz, 1H),8.44 (dd, J=8.1, 2.0 Hz, 1H), 8.28 (dd, J=8.1, 0.8 Hz, 1H), 8.05 (br s,1H), 3.98 (s, 3H), 3.06 (d, J=5.1 Hz, 3H). LRMS (ESI⁺): 195.09

Preparation of Compound 119, 6-(methylcarbamoyl)nicotinic acid

LiOH (1.984 M, 3.13 mL, 6.22 mmol) was added to a solution of Compound118 (0.483 g, 2.49 mmol) in THF (13 mL) and MeOH (3 mL). The reactionmixture was stirred at rt overnight, concentrated to remove organicsolvents, diluted with water, and washed with EtOAc (1×). The aqueousphase was acidified to pH 3 with 2 M HCl, and the resulting precipitatewas isolated by filtration, washed with water and dried to afford thetitle compound (321 mg, 72%) as a white solid. ¹H NMR (500 MHz, DMSO) δ13.67 (br s, 1H), 9.07 (dd, J=2.1, 0.7 Hz, 1H), 8.95-8.91 (m, 1H), 8.43(dd, J=8.1, 2.1 Hz, 1H), 8.13 (dd, J=8.1, 0.7 Hz, 1H), 2.83 (d, J=4.9Hz, 3H). HRMS (ESI⁺): calcd for C₃H₉N₂O₃(M+H)⁺, 181.0608; found181.0608.

Preparation of Compound 120, tert-butyl(3-((6-bromoquinolin-2-yl)oxy)propyl)carbamate

This was prepared as for Compound 3, substituting tert-butylN-(3-hydroxypropyl)carbamate for (R)-(−)-1-methyl-3-hydroxypyrrolidine.The crude material was purified by silica gel column chromatographyusing a gradient of 15 to 25% MeOH in DCM to afford the title compoundas an off-white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.90 (d, J=8.8 Hz, 1H),7.86 (d, J=2.2 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 7.68 (dd, J=8.9, 2.1 Hz,1H), 6.91 (d, J=8.9 Hz, 1H), 4.56 (t, J=6.1 Hz, 2H), 3.30 (br s, 2H),2.01 (p, J=6.3 Hz, 2H), 1.45 (s, 9H). HRMS (ESI⁺): calcd for C₁₇H₂₂⁷⁹BrN₂O₃(M+H)⁺, 381.0808; found 381.0786.

Preparation of Compound 121,2-(3-((tert-butoxycarbonyl)amino)propoxy)quinoline-6-carboxylic acid

This was prepared as for Compound 4, substituting Compound 120 forCompound 3. After acidification of the aqueous phase, it was extractedwith DCM (3×), dried (MgSO₄), filtered and concentrated to afford thetitle compound as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.52 (s, 1H),8.25 (d, J=7.8 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.91-7.84 (m, 2H), 6.96(d, J=9.1 Hz, 1H), 4.63-4.58 (m, 2H), 3.32 (t, J=6.5 Hz, 2H), 2.03 (p,J=6.3 Hz, 2H), 1.46 (s, 9H). HRMS (ESI⁺): calcd for C₁₈H₂₃N₂O₅ (M+H)⁺,347.1602; found 347.1607.

Example 90—Preparation ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-6-carboxamide

A solution of HATU (122 mg, 0.32 mmol) in DMA (1 mL) was added to astirred mixture of Compound 2 (70 mg, 0.25 mmol),2-(trifluoromethyl)-3H-benzimidazole-5-carboxylic acid (0.49 mmol) andDIPEA (0.172 mL, 0.98 mmol) in DMA (1 mL) at ambient temperature. Theresulting mixture was stirred at ambient temperature for 1 hour and thenat 60° C. for 2 hours before being allowed to cool. The crude productwas purified by preparative HPLC. Fractions containing the desiredcompound were evaporated to dryness to afford the desired material as asolid (67 mg, 55%). ¹H NMR (400 MHz, DMSO) δ 14.24 (s, 1H), 10.02 (m,2H), 8.42 (s, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.86 (s, 1H), 7.44-7.67 (m,4H), 7.24 (d, J=8.6 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.2-4.42 (m, 4H),2.24 (s, 3H). m/z (ES+) (M+H)+=497.37.

Examples 91 to 100

The following compounds were synthesised according to the procedure forExample 90, by substituting the appropriate carboxylic acid for2-(trifluoromethyl)-3H-benzimidazole-5-carboxylic acid.

-   Example 91,    2-amino-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)benzo[d]thiazole-6-carboxamide-   Example 92,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxamide-   Example 93,    N-(3-(4-hydroxybenzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 94,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(phenylamino)nicotinamide-   Example 95,    2-amino-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-4-methoxybenzo[d]thiazole-6-carboxamide-   Example 96,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(1H-1,2,4-triazol-1-yl)isonicotinamide-   Example 97,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1H-indazole-5-carboxamide-   Example 98,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-morpholinoisonicotinamide-   Example 99,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide-   Example 100,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide-   Table C

TABLE C 1H NMR Mass Spec Example ¹H NMR (400 MHz, DMSO) δ 10.03 (s, 1H),9.73 (s, 1H), 8.30 (s, 1H), m/z (ES−) 91 7.89 (dd, J = 1.9, 8.4 Hz, 1H),7.83 (d, J = 2.2 Hz, 1H), 7.77 (s, 1H), (M − H)− = 7.47-7.62 (m, 2H),7.41 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 459.55 6.97 (dd, J =8.3, 11.0 Hz, 1H), 4.14-4.47 m, 4H), 1.99 (s, 3H). Example ¹H NMR (400MHz, DMSO) δ 13.20 (s, 1H), 10.04 (d, J = 4.8 Hz, 2H), m/z (ES+) 92 9.00(s, 1H), 8.60 (s, 2H), 7.87 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 2.2, (M +H)+ = 8.3 Hz, 1H), 7.47-7.58 (m, 2H), 7.24 (d, J = 8.5 Hz, 1H), 6.98 (d,J = 430.4 8.4 Hz, 1H), 4.23-4.4 (m, 4H), 2.25 (s, 3H). Example ¹H NMR(400 MHz, DMSO) δ 10.01 (s, 1H), 9.61 (s, 1H), 7.84-7.91 m/z (ES+) 93(m, 2H), 7.80 (d, J = 2.5 Hz, 1H), 7.42-7.61 (m, 4H), 7.20 (d, J = 8.5(M + H)+ = Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.82-6.91 (m, 2H),4.25-4.41 (m, 405.41 4H), 2.19 (s, 3H). Example ¹H NMR (400 MHz, DMSO) δ10.03 (s, 1H), 9.71 (s, 1H), 9.45 (s, m/z (ES+) 94 1H), 8.82 (d, J = 2.4Hz, 1H), 8.11 (dd, J = 2.5, 8.8 Hz, 1H), 7.84 (d, J = (M + H)+ = 2.3 Hz,1H), 7.66-7.8 (m, 2H), 7.48-7.65 (m, 3H), 7.28-7.38 481.44 (m, 2H), 7.22(d, J = 8.5 Hz, 1H), 6.98 (m, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.32 (m,4H), 2.22 (s, 3H). Example ¹H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 9.75(s, 1H), 7.95 (d, J = m/z (ES−) 95 1.24 Hz, 1H), 7.82 (d, J = 2.21 Hz,1H), 7.68 (s, 2H), 7.43-7.61 (m, (M − H)− = 4H), 7.21 (d, J = 8.5 Hz,1H), 6.98 (d, J = 8.4 Hz, 1H), 4.18-4.42 (m, 489 4H), 3.92 (s, 3H), 2.21(s, 3H). Example ¹H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 10.06 (s, 1H),9.45 (s, m/z (ES−) 96 1H), 8.76 (d, J = 5.0 Hz, 1H), 8.38 (s, 1H), 7.99(d, J = 5.21 Hz, 1H), (M − H)− = 7.87 (s, 1H), 7.60 (dd, J = 2.2, 8.3Hz, 1H), 7.44-7.55 (m, 3H), 7.25 455 (d, J = 8.4 Hz, 1H), 6.98 (d, J =8.4 Hz, 1H), 4.31 (m, 4H), 2.22 (s, 3H). Example ¹H NMR (400 MHz, DMSO)δ 13.31 (s, 1H), 10.03 (s, 1H), 9.88 (s, m/z (ES−) 97 1H), 9.68 (s, 1H),8.51 (s, 1H), 8.26 (s, 1H), 7.94-8.06 (d, 1H), 7.85 (M − H)− = (d, J =2.3 Hz, 1H), 7.63 (d, J = 8.78 Hz, 1H), 7.55-7.6 (m, 1H), 7.51- 427 7.54(m, 1H). 7.23 (d, J = 8.6 Hz, 1H), 6.97 (dd, J = 8.3, 11.9 Hz, 1H),4.23-4.45 (m, 4H), 2.24 (s, 3H). Example ¹H NMR (400 MHz, DMSO) δ 10.03(m, 2H), 8.30 (d, J = 5.2 Hz, 1H), m/z (ES−) 98 7.83 (t, J = 2.7, 2.7Hz, 1H), 7.58 (dd, J = 2.2, 8.3 Hz, 1H), 7.44- (M − H)− = 7.55 (m, 2H),7.31 (s, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 5.1 473 Hz, 1H),6.98 (d, J = 8.3 Hz, 1H), 4.32 (m, 4H), 3.65-3.85 (m, 4H), 3.49-3.63 (m,4H), 2.19 (s, 3H). Example ¹H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 10.03(s, 1H), 9.84 (s, m/z (ES−) 99 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.41 (d, J= 2.0 Hz, 1H), 7.85 (d, J = 2.4 (M − H)− = Hz, 1H), 7.45-7.66 (m, 3H),7.22 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 8.4 442 Hz, 1H), 6.30 (s, 1H),4.16-4.43 (m, 4H), 2.43 (s, 3H), 2.24 (s, 3H). Example ¹H NMR (400 MHz,DMSO) δ 11.95 (s, 1H), 10.04 (s, 1H), 9.90 (s, m/z (ES−) 100 1H), 8.86(d, J = 2.1 Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 2.4 (M − H)−= Hz, 1H), 7.38-7.69 (m, 4H), 7.23 (d, J = 8.5 Hz, 1H), 7.0 (d, J = 8.4427 Hz, 1H), 6.55-6.65 (m, 1H), 4.26-4.39 (m, 4H), 2.24 (s, 3H).

Example 101—Preparation ofN-(4-methyl-3-(4-(thiazol-4-ylmethoxy)benzamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

HATU (0.321 g, 0.840 mmol) and DIPEA (0.368 mL, 2.11 mmol) were added toa solution of 4-(thiazol-4-ylmethoxy)benzoic acid (0.199 g, 0.840 mmol)in DMA (3 mL) under an inert atmosphere and the reaction allowed to stirfor 15 minutes. Compound 2 (0.200 g, 0.700 mmol) was added and thereaction mixture was stirred at ambient temperature overnight. Thereaction was diluted with water and the solids filtered. The solids weredissolved in DMF and purified by preparative HPLC. Fractions containingthe desired compound were evaporated to dryness to afford the desiredmaterial as a white solid (0.184 g, 52%). ¹H NMR (400 MHz, DMSO) δ 10.02(s, 1H), 9.73 (s, 1H), 9.14 (d, J=2.00 Hz, 1H), 8.06-7.94 (m, 2H), 7.82(dd, J=2.1, 11.8 Hz, 2H), 7.64-7.43 (m, 3H), 7.26-7.10 (m, 3H), 6.97 (d,J=8.4 Hz, 1H), 5.32 (s, 2H), 4.45-4.13 (m, 4H), 2.19 (s, 3H). m/z (ES+)(M+H)+=502.

Examples 102 to 112

The following compounds were synthesised according to the procedure forExample 101, by substituting the appropriate carboxylic acid for4-(thiazol-4-ylmethoxy)benzoic acid.

-   Example 102,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(ethylamino)nicotinamide-   Example 103,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxamide-   Example 104,    6-amino-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)nicotinamide-   Example 105,    2-amino-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)isonicotinamide-   Example 106,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(1H-pyrazol-1-yl)nicotinamide-   Example 107,    N-(3-(4-(1H-pyrazol-1-yl)benzamido)-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 108,    N-(4-methyl-3-(6-methyl-2-naphthamido)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide-   Example 109,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-3-methyl-4-oxo-3,4-dihydroquinazoline-6-carboxamide-   Example 110,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-4-(2-(dimethylamino)ethylamino)-2-methylquinoline-6-carboxamide-   Example 111,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-4-(3-(dimethylamino)propylamino)-2-methylquinoline-6-carboxamide-   Example 112,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-4-(methyl(1-methylpyrrolidin-3-yl)amino)quinoline-6-carboxamide

TABLE D 1H NMR Mass Spec Example ¹H NMR (400 MHz, DMSO) δ 10.00 (s, 1H),9.51 (s, 1H), 8.66 (d, J = m/z (ES+) 102 2.4 Hz, 1H), 7.91 (dd, J = 2.4,8.8 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), (M + H)+ = 7.61-7.45 (m, 3H),7.19 (d, J = 8.5 Hz, 1H), 7.10 (t, J = 5.4, 5.4 Hz, 433 1H), 6.97 (d, J= 8.4 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 4.4-4.2 (m, 4H), 3.40-3.20 (m,2H), 2.18 (s, 3H), 1.16 (t, J = 7.2, 7.2 Hz, 3H). Example ¹H NMR (400MHz, DMSO) δ 10.32 (s, 1H), 10.02 (s, 1H), 9.71 (s, 1H), m/z (ES+) 1037.92-7.71 (m, 3H), 7.65-7.44 (m, 3H), 7.20 (d, J = 8.5 Hz, 1H), 7.02-(M + H)+ = 6.88 (m, 2H), 4.41-4.18 (m, 4H), 2.97 (t, J = 7.5, 7.5 Hz,2H), 2.57- 458 2.45 (m, 2H), 2.18 (s, 3H). Example ¹H NMR (400 MHz,DMSO) δ 10.00 (s, 1H), 9.53 (s, 1H), 8.60 (d, J = m/z (ES+) 104 2.16 Hz,1H), 7.93 (dd, J = 2.5, 8.7 Hz, 1H), 7.79 (d, J = 2.2 Hz, 1H), (M + H)+= 7.60-7.40 (m, 3H), 7.19 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H),405 6.54 (s, 2H), 6.48 (d, J = 8.39 Hz, 1H), 4.39-4.19 (m, 4H), 2.18 (s,3H). Example ¹H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 9.90 (s, 1H), 8.05(d, J = m/z (ES+) 105 5.2 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.58 (dd, J= 2.1, 8.3 Hz, 1H), (M + H)+ = 7.54-7.45 (m, 2H), 7.21 (d, J = 8.5 Hz,1H), 7.07-6.75 (m, 3H), 6.16 405 (s, 2H), 4.24-4.36 (m, 4H), 2.18 (s,3H). Example ¹H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 9.83 (s, 1H), 8.83(d, J = 1.8 m/z (ES+), 106 Hz, 1H), 8.47-8.54 (m, 1H), 8.31 (dd, J =2.3, 8.6 Hz, 1H), 7.85 (d, J = (M + H)+ = 9.1 Hz, 1H), 7.69 (d, J = 1.0Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.37 456 (dd, J = 2.2, 8.3 Hz, 1H),7.25-7.34 (m, 2H), 7.03 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H),6.43 (dd, J = 1.7, 2.6 Hz, 1H), 4.05-4.15 (m, 4H), 2.01 (s, 3H). Example¹H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 9.95 (s, 1H), 8.64 (d, J = m/z(ES+), 107 2.5 Hz, 1H), 8.1-8.15 (m, 2H), 7.98-8.05 (m, 2H), 7.85 (d, J= 2.2 (M + H)+ = Hz, 1H), 7.83 (d, J = 1.7 Hz, 1H), 7.59 (dd, J = 2.1,8.3 Hz, 1H), 7.49- 455 7.56 (m, 2H), 7.24 (d, J = 8.5 Hz, 1H), 6.98 (d,J = 8.4 Hz, 1H), 6.62 (dd, J = 1.8, 2.4 Hz, 1H), 4.28-4.35 (m, 4H), 2.23(s, 3H). Example ¹H NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 10.08 (s, 1H),8.62 (s, 1H), m/z (ES+), 108 7.98-8.12 (m, 3H), 7.93 (d, J = 2.2 Hz,1H), 7.85 (s, 1H), 7.65 (dd, J = (M + H)+ = 2.2, 8.3 Hz, 1H), 7.5-7.62(m, 3H), 7.30 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 453 8.4 Hz, 1H),4.34-4.42 (m, 4H), 2.58 (s, 3H), 2.31 (s, 3H). Example ¹H NMR (400 MHz,DMSO) δ 10.27 (s, 1H), 10.07 (s, 1H), 8.83 (d, J = m/z (ES+) 109 2.1 Hz,1H), 8.49 (s, 1H), 8.37 (dd, J = 2.1, 8.5 Hz, 1H), 7.89-7.75 (M + H)+ =(m, 2H), 7.59 (dd, J = 2.2, 8.3 Hz, 1H), 7.56-7.44 (m, 2H), 7.23 (d, J =471 8.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.40-4.21 (m, 4H), 3.54 (s,3H), 2.21 (s, 3H). Example ¹H NMR (400 MHz, DMSO) δ 10.08 (s, 1H), 9.92(s, 1H), 8.76 (d, J = m/z (ES+) 110 1.60 Hz, 1H), 8.10 (dd, J = 1.82,8.76 Hz, 1H), 7.90 (d, J = 2.18 Hz, (M + H)+ = 1H), 7.77 (d, J = 8.75Hz, 1H), 7.45-7.62 (m, 3H), 7.24 (d, J = 8.53 540 Hz, 1H), 7.10 (t, J =5.25, 5.25 Hz, 1H), 6.99 (d, J = 8.39 Hz, 1H), 6.46 (s, 1H), 4.27-4.37(m, 4H), 3.36-3.43 (m, 2H), 3.32 (s, 3H), 2.58 (t, J = 6.74, 6.74 Hz,2H), 2.24 (s, 3H), 2.23 (s, 6H). Example ¹H NMR (400 MHz, DMSO) δ 10.04(s, 1H), 9.87 (s, 1H), 8.75 (d, J = m/z (ES+) 111 1.7 Hz, 1H), 8.10 (dd,J = 1.8, 8.7 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), (M + H)+ = 7.76 (d, J =8.7 Hz, 1H), 7.63-7.43 (m, 4H), 7.24 (d, J = 8.5 Hz, 1H), 554 6.98 (d, J= 8.4 Hz, 1H), 6.42 (s, 1H), 4.39-4.18 (m, 4H), 3.42-3.27 (m, 2H), 2.49(s, 3H), 2.38 (t, J = 6.7, 6.7 Hz, 2H), 2.24 (s, 3H), 2.19 (s, 6H), 1.83(q, J = 6.7, 6.7, 6.7, 6.7 Hz, 2H). Example ¹H NMR (400 MHz, DMSO) δ10.04 (d, J = 2.8 Hz, 2H), 10.04 (d, J = m/z (ES+) 112 2.8 Hz, 2H), 8.61(d, J = 1.7 Hz, 1H), 8.16 (dd, J = 1.9, 8.7 Hz, 1H), (M + H)+ =7.99-7.79 (m, 2H), 7.59 (dd, J = 2.1, 8.3 Hz, 1H), 7.56-7.47 (m, 5662H), 7.24 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.89 (s, 1H),4.44-4.17 (m, 5H), 2.96 (s, 3H), 2.79 (dd, J = 4.4, 9.7 Hz, 2H), 2.76-2.69 (m, 1H), 2.64-2.60 (m, 1H), 2.59 (s, 3H), 2.26 (s, 6H), 2.22- 2.10(m, 1H), 1.91-2.05 (m, 1H).

Preparation of Compound 122,N-(3-Nitrophenyl)-2,3-dihydro-1,4-benzodioxine-7-carboxamide

2,3-Dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (3.13 g, 17.38 mmol)was dissolved in DMA (25 mL) and (7.57 mL, 43.44 mmol) and HATU (6.61 g,17.38 mmol) added under an inert atmosphere. The reaction was allowed tostir for 15 minutes then 3-nitroaniline (2.0 g, 14.48 mmol) was addedand the reaction stirred at ambient temperature overnight. The reactionwas heated for a further 16 hours at 40° C. then concentrated in vacuoand water added. The solids were isolated by filtration, washed withwater and dried in a vacuum oven. The solids were stirred in EtOAc foran hour and then filtered. The filtrate was evaporated down and thesolids were triturated with DCM then filtered. The collected solids werecombined to afford the desired material as a cream solid (3.44 g, 79%).¹H NMR (400 MHz, DMSO, 30° C.) d 4.33 (4H, tq), 7.03 (1H, d), 7.53-7.59(2H, m), 7.65 (1H, t), 7.95 (1H, ddd), 8.20 (1H, ddd), 8.78-8.82 (1H,m), 10.48 (1H, s). m/z (ES+) (M+H)+=301.

Preparation of Compound 123,N-(3-Aminophenyl)-2,3-dihydro-1,4-benzodioxine-7-carboxamide

A mixture of Compound 122 (2.75 g, 9.15 mmol), palladium (10% oncharcoal, 0.487 g) in ethanol (25 mL)/EtOAc (25 mL)/THF (25 mL) werestirred under an atmosphere of hydrogen at ambient temperatureovernight. The reaction mixture was filtered through celite and thecelite was washed with THE. The filtrate and washings were combined andevaporated to afford the desired material as a light brown foam (2.62 g,106%). ¹H NMR (400 MHz, DMSO, 30° C.) d 4.28-4.35 (4H, m), 5.02 (2H, s),6.30 (1H, ddd), 6.85 (1H, ddd), 6.96 (2H, dt), 7.09 (1H, t), 7.49 (2H,qd), 9.72 (1H, s). m/z (ES+) (M+H)+=271.

Example 113,N-(3-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-methylquinoline-6-carboxamide

2-Methylquinoline-6-carboxylic acid (0.291 g, 1.55 mmol) was dissolvedin DMA (3 mL) and put under an inert atmosphere. DIPEA (0.677 mL, 3.88mmol) and HATU (0.591 g, 1.55 mmol) were added and the reaction stirredfor 15 minutes. Compound 123 (0.350 g, 1.29 mmol) was added and thereaction was stirred at ambient temperature overnight. The reaction wascooled, diluted with water and the solids filtered. The solids weredissolved in DMF and purified by preparative HPLC. Fractions containingthe desired compound were evaporated to dryness to afford the desiredmaterial as a solid (0.117 g, 21%). ¹H NMR (400 MHz, DMSO) δ 10.51 (s,1H), 10.14 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.41 (d, J=8.5 Hz, 1H),8.38-8.30 (m, 1H), 8.22 (dd, J=2.0, 8.8 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H),7.62-7.41 (m, 5H), 7.32 (t, J=8.1, 8.1 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H),4.37-4.22 (m, 4H), 2.70 (s, 3H). m/z (ES+) (M+H)+=440.

Example 114—Preparation ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)benzo[d]thiazole-6-carboxamide

HATU (695 mg, 1.83 mmol) was added to Compound 2 (400 mg, 1.41 mmol),benzo[d]thiazole-6-carboxylic acid (290 mg, 1.62 mmol) and DIPEA (0.737mL, 4.22 mmol) in DMA (15 mL) and the resultant mixture stirred atambient temperature for 16 hours under an inert atmosphere. The reactionmixture was diluted with EtOAc (300 mL), and washed with water (2×200mL). The organic layer was dried over Na₂SO₄, filtered and evaporated toafford crude product. The crude product was purified by flash silicachromatography, elution gradient 20 to 100% EtOAc in isohexane. The purefractions were evaporated to a yellow solid which was triturated withDCM and filtered to afford the desired material as a white solid (287mg, 46%). ¹H NMR (400 MHz, DMSO) δ 10.05 (s, 2H), 9.57 (s, 1H), 8.82 (d,J=1.5 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.15 (dd, J=1.74, 8.6 Hz, 1H),7.87 (d, J=2.1 Hz, 1H), 7.58-7.65 (m, 1H), 7.47-7.57 (m, 2H), 7.24 (d,J=8.42 Hz, 1H), 6.98 (d, J=8.37 Hz, 1H), 4.32 (m, 4H), 2.24 (s, 3H). m/z(ES+), (M+H)+=446.

Example 115—Preparation ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(methylamino)benzo[d]thiazole-6-carboxamide

Compound 2 (98 mg, 0.34 mmol) and4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium (173 mg,0.620 mmol) were added to a solution of2-(methylamino)benzo[d]thiazole-6-carboxylic acid (65 mg, 0.31 mmol) inDMF (4 mL) and the resultant solution stirred at ambient temperatureovernight. The reaction was diluted with water and the solids filtered.The solids were dissolved in DMF and purified by preparative HPLC.Fractions containing the desired compound were evaporated to dryness toafford the desired material as a white solid (19 mg, 13%). ¹H NMR (400MHz, DMSO) δ 10.06 (s, 1H), 9.78 (s, 1H), 8.32 (d, J=1.7 Hz, 1H), 8.27(q, J=4.6 Hz, 1H), 7.89 (dd, J=1.9, 8.4 Hz, 1H), 7.82 (d, J=2.1 Hz, 1H),7.57 (dd, J=2.2, 8.3 Hz, 1H), 7.51-7.55 (m, 2H), 7.47 (d, J=8.4 Hz, 1H),7.21 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.27-4.36 (m, 4H), 2.99(d, J=4.7 Hz, 3H), 2.21 (s, 3H). m/z (ES+), (M+H)+=475.

Example 116,2-amino-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)benzo[d]thiazole-7-carboxamide

HATU (0.201 g, 0.53 mmol) and DIPEA (0.230 mL, 1.32 mmol) were added toa solution of 2-aminobenzo[d]thiazole-7-carboxylic acid (102 mg, 0.53mmol) in DMA (3 mL) under an inert atmosphere and the reaction allowedto stir for 15 minutes. Compound 2 (0.125 g, 0.440 mmol) was added andthe reaction stirred at ambient temperature for approximately 24 hoursand then at 40° C. overnight. No product was observed. Additional2-aminobenzo[d]thiazole-7-carboxylic acid (102 mg, 0.53 mmol) wasconverted to the acid chloride by treatment with oxalyl chloride(approximately 1.2 equivalents) and DMF (a few drops) in DCM and theacid chloride added to the reaction mixture. The reaction was dilutedwith water and the solids filtered. The solids were dissolved in DMF andpurified by preparative HPLC. Fractions containing the desired compoundwere evaporated to dryness to afford the desired material as a whitesolid (0.043 g, 21%). ¹H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 10.04 (s,1H), 7.87 (d, J=7.1 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.62 (dd, J=2.2,8.3 Hz, 1H), 7.49-7.56 (m, 3H), 7.47 (s, 2H), 7.39 (t, J=7.8 Hz, 1H),7.25 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.28-4.35 (m, 4H), 2.21(s, 3H). m/z (ES+), (M+H)+=461.

Preparation of Compound 124, ethyl4-(2-dimethylaminoethylamino)-2-methylquinoline-6-carboxylate

Ethyl 4-chloro-2-methylquinoline-6-carboxylate (0.355 g, 1.42 mmol),N,N-dimethylethane-1,2-diamine (0.783 mL, 7.11 mmol) and DIPEA (2.476mL, 14.22 mmol) were combined in NMP (8 mL) and sealed in a microwavetube. The reaction was heated at 200° C. for 1 hour. The crude productwas purified by preparative HPLC. Fractions containing the desiredcompound were evaporated to dryness to afford the desired material as agum (0.163 g, 38%). ¹H NMR (400 MHz, CDCl3, 30° C.) d 1.38 (3H, t), 2.27(6H, s), 2.57 (3H, s), 2.59-2.68 (2H, t), 3.26 (2H, q), 4.37 (2H, q),6.06 (1H, s), 6.26 (1H, s), 7.84 (1H, d), 8.12 (1H, dd), 8.55 (1H, d).m/z (ES+) (M+H)+=302.

Preparation of Compound 125,4-(2-dimethylaminoethylamino)-2-methylquinoline-6-carboxylic acid

Sodium hydroxide (2.00 M, 5.13 mL, 10.3 mmol) was added to a solution ofCompound 124 (0.163 g, 0.54 mmol) in dioxane (5 mL) and stirred at 40°C. overnight. The reaction was neutralized to pH 7 with 2M hydrochloricacid and the solvent removed in vacuo to afford the desired material asa solid (0.148 g) which was used without further purification. ¹H NMR(400 MHz, DMSO, 30° C.) d 2.60 (9H, bd), 3.06 (2H, bt), 3.71 (2H, bs),6.75 (1H, s), 7.89 (1H, d), 8.12-8.20 (1H, m), 8.61 (1H, bs), 9.02 (1H,s), 13.21 (1H, bs). m/z (ES+) (M+H)+=274.

Preparation of Compound 126, ethyl4-(3-dimethylaminopropylamino)-2-methylquinoline-6-carboxylate

Ethyl 4-chloro-2-methylquinoline-6-carboxylate (0.352 g, 1.41 mmol),N,N-dimethylpropane-1,3-diamine (0.719 mL, 7.04 mmol) and DIPEA (2.452mL, 14.08 mmol) were combined in NMP (8 mL) and sealed in a microwavetube. The reaction was heated at 200° C. for 1 hour. The crude productwas purified by preparative HPLC. Fractions containing the desiredcompound were evaporated to dryness to afford the desired material as agum (0.205 g, 46%). ¹H NMR (400 MHz, CDCl3, 30° C.) d 1.31 (3H, t),1.73-1.81 (2H, m), 2.31 (6H, s), 2.44-2.48 (2H, m), 2.49 (3H, s),3.20-3.27 (2H, m), 4.28-4.35 (2H, q), 6.09 (1H, s), 7.74-7.79 (1H, m),8.06 (1H, dd), 8.38 (1H, d), 8.45 (1H, s). m/z (ES+) (M+H)+=316.

Preparation of Compound 127,4-(3-dimethylaminopropylamino)-2-methylquinoline-6-carboxylic acid

Sodium hydroxide (2.00M, 6.16 mL, 12.3 mmol) was added to a solution ofCompound 126 (0.205 g, 0.650 mmol) in dioxane (5 mL) and stirred at 40°C. overnight. The reaction was neutralized to pH 7 with 2M hydrochloricacid and the solvent removed in vacuo to afford the desired material asa solid (0.186 g) which was used without further purification. ¹H NMR(400 MHz, DMSO, 30° C.) d 2.06 (2H, q), 2.62 (9H, bd), 3.00 (2H, t),3.54 (2H, d), 6.69 (1H, s), 7.92 (1H, d), 8.21 (1H, t), 8.86 (1H, bs),9.11 (1H, s), 12.39-13.53 (1H, bs). m/z (ES+) (M+H)+=288.

Preparation of Compound 128, ethyl2-methyl-4-[methyl-(1-methylpyrrolidin-3-yl)amino]quinoline-6-carboxylate

Ethyl 4-chloro-2-methylquinoline-6-carboxylate (0.270 g, 1.08 mmol),N,1-dimethylpyrrolidin-3-amine (0.702 mL, 5.41 mmol) and DIPEA (1.883mL, 10.81 mmol) were combined in NMP (8 mL) and sealed in a microwavetube. The reaction was heated at 200° C. for 1 hour. The crude productwas purified by preparative HPLC. Fractions containing the desiredcompound were evaporated to dryness to afford the desired material as agum (0.066 g, 19%). ¹H NMR (400 MHz, CDCl3, 30° C.) d 1.43 (3H, t), 2.06(1H, tt), 2.18-2.30 (1H, m), 2.35 (3H, d), 2.40-2.49 (1H, m), 2.63-2.67(3H, m), 2.67-2.87 (4H, m), 2.98 (3H, d), 4.42 (2H, q), 6.67 (1H, d),7.94 (1H, dd), 8.16 (1H, dt), 8.76 (1H, d). m/z (ES+) (M+H)+=328.

Preparation of Compound 129,2-methyl-4-[methyl-(1-methylpyrrolidin-3-yl)amino]quinoline-6-carboxylicacid

Sodium hydroxide (1.924 mL, 3.85 mmol) was added to a solution ofCompound 128 (0.066 g, 0.20 mmol) in dioxane (5 mL) and stirred at 40°C. overnight. The reaction was neutralized to pH 7 with 2M hydrochloricacid and the solvent removed in vacuo to afford the desired material asa solid (0.061 g) which was used without further purification. ¹H NMR(400 MHz, DMSO, 30° C.) d 2.09-2.21 (1H, m), 2.28 (1H, m), 2.62 (6H, d),2.97 (3H, s), 3.22 (4H, m), 4.41-4.52 (1H, m), 6.98 (1H, s), 7.90 (1H,d), 8.10 (1H, dd), 8.65 (1H, d), 12.27-12.75 (1H, bs). m/z (ES+)(M+H)+=277.

Preparation of Compound 130, 4-chloro-2-methylquinoline-6-carboxylicacid hydrochloride

A mixture of Compound 57 (0.500 g, 2.12 mmol) in HCl (37%, 9.5 mL) washeated to 95° C. for 1 hr, then concentrated to afford the titlecompound (519 mg, 95%) as a pale purple solid. ¹H NMR (500 MHz, DMSO) δ8.77 (d, J=1.7 Hz, 1H), 8.32 (dd, J=8.8, 1.9 Hz, 1H), 8.15 (d, J=8.8 Hz,1H), 7.91 (s, 1H), 2.75 (s, 3H). HRMS (ESI⁺): calcd for C₁₁H₉NO₂ (M+H)⁺,222.0322; found 222.0312.

Preparation of Compound 131,N-[5-(2,3-Dihydro-1,4-benzodioxine-7-carbonylamino)-2-methylphenyl]-2-methyl-4-(triazolo[5,4-b]pyridin-3-yloxy)quinoline-6-carboxamide

HATU (1.384 g, 3.64 mmol) was added to a stirred solution of Compound130 (783 mg, 3.03 mmol) and DIPEA (1.585 mL, 9.10 mmol) in DMF (8 mL).After 2-3 minutes a thick suspension formed and Compound 2 (863 mg, 3.03mmol) was added followed by DMF (8 mL). The resulting suspension wasstirred at ambient temperature overnight then the reaction quenched withwater (50 mL) and the precipitate was collected by filtration. The solidwas washed with water (10 mL) and dried under vacuum to afford the crudedesired material as a brown solid (2.14 g) which was used in subsequentreactions without further purification. ¹H NMR (400 MHz, DMSO, 20° C.)2.25 (3H, s), 2.55 (3H, s), 4.21-4.38 (4H, m), 6.85 (1H, s), 6.98 (1H,d), 7.25 (1H, d), 7.5-7.57 (2H, m), 7.60 (1H, dd), 7.73 (1H, dd), 7.88(1H, d), 7.95 (1H, s), 8.18 (1H, d), 8.44 (1H, dd), 8.81-8.89 (1H, m),9.10 (1H, d), 10.09 (1H, s), 10.42 (1H, s). m/z (ES+) (M+H)+=588.

Example 117,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-4-(2-(pyrrolidin-1-yl)ethylamino)quinoline-6-carboxamide

Compound 131 (160 mg, 0.27 mmol) and 2-pyrrolidin-1-ylethanamine (0.82mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Thereaction was heated to 120° C. for 30 minutes in the microwave reactorand cooled to RT. The reaction mixtures were purified by preparativeHPLC. Fractions containing the desired compound were evaporated todryness to afford the desired material as a solid (9 mg, 6%). ¹H NMR(700 MHz, DMSO) δ 10.05 (s, 1H), 9.87 (s, 1H), 8.78 (d, J=1.8 Hz, 1H),8.11 (dd, J=1.9, 8.7 Hz, 1H), 7.90 (s, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.56(d, J=8.4 Hz, 1H), 7.54 (s, 1H), 7.5-7.54 (m, 1H), 7.25 (d, J=8.5 Hz,1H), 7.18 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.28-4.35 (m, 4H), 3.42-3.46(m, 3H), 2.78 (t, J=6.9 Hz, 2H), 2.55-2.60 (m, 4H), 2.55 (s, 3H), 2.25(s, 3H), 1.69-1.75 (m, 4H). m/z (ES+) (M+H)+=566.

Example 118—Preparation ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-4-(2-morpholinoethylamino)quinoline-6-carboxamide

This was prepared as for Example 117, substituting2-morpholinoethanamine for 2-pyrrolidin-1-ylethanamine. ¹H NMR (700 MHz,DMSO) δ 10.05 (s, 1H), 9.91 (s, 1H), 8.80 (d, J=1.8 Hz, 1H), 8.13 (dd,J=1.8, 8.7 Hz, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.57(dd, J=2.2, 8.2 Hz, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.52 (dd, J=2.2, 8.4Hz, 1H), 7.30 (s, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H),6.52 (s, 1H), 4.27-4.35 (m, 4H), 3.6-3.63 (m, 4H), 3.46 (t, J=6.3 Hz,2H), 2.67 (t, J=6.9 Hz, 2H), 2.52 (s, 3H), 2.49-2.52 (m, 4H), 2.26 (s,3H). m/z (ES+) (M+H)+=582.

Example 119,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methylquinoline-6-carboxamide

This was prepared as for Example 117, substitutingN¹,N¹,N²-trimethylethane-1,2-diamine for 2-pyrrolidin-1-ylethanamine. ¹HNMR (700 MHz, DMSO) δ 10.04 (s, 2H), 8.68 (d, J=1.8 Hz, 1H), 8.16 (dd,J=2.0, 8.7 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.58(dd, J=2.1, 8.2 Hz, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.52 (dd, J=2.2, 8.5Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.91 (s, 1H),4.28-4.35 (m, 4H), 3.43 (t, J=7.0 Hz, 2H), 3.03 (s, 4H), 2.72 (t, J=6.9Hz, 2H), 2.60 (s, 3H), 2.24 (s, 3H), 2.19 (s, 6H). m/z (ES+) (M+H)+=554.

Example 120—Preparation ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide

2-(Pyrrolidin-1-yl)ethanol (0.090 mL, 0.77 mmol) was added to a stirredsuspension of sodium hydride (60% in mineral oil, 30.6 mg, 0.77 mmol) inDMA (2 mL) under an inert atmosphere and the resulting solution stirredat ambient temperature for 5 minutes. Compound 131 (150 mg, 0.26 mmol)was added and the mixture stirred at 70° C. for 1 hour. The reaction wasquenched with water (2 mL) and the mixture purified by ion exchangechromatography, using an SCX column with the desired product eluted fromthe column using 7M NH₃/MeOH. Pure fractions were evaporated to drynessto afford a brown gum which was further purified by preparative HPLC.Fractions containing the desired compound were evaporated to dryness toafford the desired material as a white solid (20 mg, 14%). ¹H NMR (400MHz, DMSO) δ 10.11 (s, 1H), 10.04 (s, 1H), 8.74 (d, J=1.9 Hz, 1H), 8.23(dd, J=2.0, 8.8 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H),7.60 (dd, J=2.2, 8.3 Hz, 1H), 7.48-7.57 (m, 2H), 7.25 (d, J=8.5 Hz, 1H),7.06 (s, 1H), 6.99 (d, J=8.4 Hz, 1H), 4.40 (t, J=5.7 Hz, 2H), 4.24-4.36(m, 4H), 3.01 (t, J=5.7 Hz, 2H), 2.58-2.67 (m, 7H), 2.25 (s, 3H),1.65-1.76 (m, 4H). m/z (ES+) (M+H)+=567.

Preparation of Compound 132,6-chloro-N-[5-(2,3-dihydro-1,4-benzodioxine-7-carbonylamino)-2-methylphenyl]pyridine-3-carboxamide

6-Chloronicotinoyl chloride (201 mg, 1.14 mmol) was added to Compound 2(295 mg, 1.04 mmol) and pyridine (0.126 mL, 1.56 mmol) in DCM (20 mL)under an inert atmosphere and the resulting solution stirred at ambienttemperature for 2 hours. The reaction mixture was washed sequentiallywith water (2×20 mL) and a saturated solution of sodium bicarbonate (20mL), the organic layer was dried over MgSO₄, filtered and evaporated.The solid was triturated with diethyl ether and filtered to afford thedesired material as a solid (348 mg, 79%). ¹H NMR (400 MHz, DMSO, 30°C.) d 2.21 (3H, s), 4.31 (4H, q), 6.98 (1H, d), 7.24 (1H, d), 7.42-7.64(3H, m), 7.72 (1H, d), 7.86 (1H, d), 8.37 (1H, dd), 8.98 (1H, d), 10.05(1H, s), 10.16 (1H, s). m/z (ES+) (M+H)+=424.

Preparation of Example 121,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-(1-methylpiperidin-4-yloxy)phenylamino)nicotinamide

A mixture of Compound 132 (50 mg, 0.12 mmol),3-(1-methylpiperidin-4-yloxy)aniline (36.5 mg, 0.18 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.10 mg,0.0071 mmol), tris(dibenzylideneacetone)dipalladium (0) (3.24 mg, 0.0035mmol), sodium 2-methylpropan-2-olate (17 mg, 0.18 mmol) in toluene (2mL) and isopropyl alcohol (0.5 mL) was degassed with nitrogen and heatedat reflux for 18 hours. The reaction mixture was diluted with EtOAc (100mL), washed with water (100 mL), the organic layer dried over Na₂SO₄,filtered and evaporated to afford crude product. The crude product waspurified by flash silica chromatography, elution gradient 0 to 30%MeOH/7M NH₃ in EtOAc to give crude material which was further purifiedby preparative HPLC. Fractions containing the desired compound wereevaporated to dryness to afford the desired material as a cream solid(23 mg, 33%). ¹H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 9.71 (s, 1H), 9.41(s, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.10 (dd, J=2.5, 8.8 Hz, 1H), 7.83 (d,J=2.3 Hz, 1H), 7.39-7.65 (m, 5H), 7.14-7.25 (m, 2H), 6.97 (d, J=8.4 Hz,1H), 6.89 (d, J=8.8 Hz, 1H), 6.56 (dd, J=2.2, 2.2, 6.9 Hz, 1H), 4.31 (m,4H), 2.58-2.71 (m, 4H), 2.20 (s, 3H), 2.18 (s, 3H), 1.96 (m, 2H), 1.66(m, 2H). m/z (ES+) (M+H)+=594.

Example 122,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-(4-methylpiperazin-1-yl)propylamino)nicotinamide

A mixture of Compound 132 (50 mg, 0.12 mmol),3-(4-methylpiperazin-1-yl)propan-1-amine (27.8 mg, 0.18 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.10 mg,0.0071 mmol), tris(dibenzylideneacetone)dipalladium (O) (3.24 mg, 0.0035mmol), sodium 2-methylpropan-2-olate (17 mg, 0.18 mmol) in toluene (2mL) and isopropyl alcohol (0.5 mL) was degassed with nitrogen and heatedat reflux for 18 hours. The reaction mixture was diluted with EtOAc (100mL), washed with water (100 mL), the organic layer dried over Na₂SO₄,filtered and evaporated to afford crude product. The crude product waspurified by preparative HPLC. Fractions containing the desired compoundwere evaporated to dryness to afford the desired material as acolourless gum (2 mg, 3%). ¹H NMR (400 MHz, CDCl₃) δ 8.62 (s, 1H), 8.10(d, J=9.32 Hz, 2H), 7.92 (d, J=6.46 Hz, 1H), 7.75 (s, 1H), 7.69 (d,J=8.28 Hz, 1H), 7.55 (s, 1H), 7.43 (d, J=2.15 Hz, 1H), 7.36 (dd, J=2.20,8.44 Hz, 1H), 7.21 (d, J=8.32 Hz, 1H), 6.94 (d, J=8.41 Hz, 1H), 6.50 (d,J=8.80 Hz, 1H), 4.50-4.13 (m, 4H), 3.59-3.47 (m, 2H), 3.04-2.84 (m, 6H),2.83-2.64 (m, 2H), 2.55 (s, 3H), 2.31 (s, 3H), 2.00-1.87 (m, 2H),0.96-0.71 (m, 2H). m/z (ES+) (M+H)+=545.

Example 123,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-((4-methylpiperazin-1-yl)methyl)phenylamino)nicotinamide

This was prepared as for Example 122, substituting3-((4-methylpiperazin-1-yl)methyl)aniline for3-(4-methylpiperazin-1-yl)propan-1-amine. ¹H NMR (400 MHz, DMSO) δ 10.02(s, 1H), 9.70 (s, 1H), 9.44 (s, 1H), 8.81 (d, J=2.4 Hz, 1H), 8.09 (dd,J=2.5, 8.8 Hz, 1H), 7.83 (d, J=2.2 Hz, 1H), 7.71 (d, J=9.3 Hz, 1H),7.42-7.6 (m, 5H), 7.26 (d, J=7.8 Hz, 1H), 7.17-7.23 (m, 1H), 6.97 (d,J=8.4 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 4.23-4.42 (m, 4H), 3.44 (s, 2H),3.28 (m, 8H), 2.21 (s, 3H), 2.16 (s, 3H). m/z (ES+) (M+H)+=593.

Example 124,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-((dimethylamino)methyl)phenylamino)nicotinamide

This was prepared as for Example 122, substituting3-((dimethylamino)methyl)aniline for3-(4-methylpiperazin-1-yl)propan-1-amine. ¹H NMR (400 MHz, DMSO) δ 10.02(s, 1H), 9.70 (s, 1H), 9.43 (s, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.09 (dd,J=2.5, 8.8 Hz, 1H), 7.95 (s, 1H), 7.83 (d, J=2.2 Hz, 1H), 7.68 (dd,J=8.0 Hz, 1H), 7.47-7.64 (m, 4H), 7.18-7.24 (m, 2H), 6.97 (d, J=8.4 Hz,1H), 6.89 (d, J=8.3 Hz, 1H), 4.22-4.38 (m, 4H), 3.0 (s, 2H), 2.33 (s,3H), 2.23 (s, 6H). m/z (ES+) (M+H)+=538.

Example 125,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-(3-(dimethylamino)pyrrolidin-1-yl)phenylamino)nicotinamide

This was prepared as for Example 122, substituting1-(3-aminophenyl)-N,N-dimethylpyrrolidin-3-amine for3-(4-methylpiperazin-1-yl)propan-1-amine. ¹H NMR (400 MHz, DMSO) δ 10.02(s, 1H), 9.71 (s, 1H), 9.25 (s, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.10 (dd,J=2.5, 8.8 Hz, 1H), 7.83 (d, J=2.3 Hz, 1H), 7.39-7.65 (m, 5H), 7.14-7.25(m, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.22 (dd,J=2.2, 2.2, 6.9 Hz, 1H), 4.31 (m, 4H), 3.28 (m, 6H), 2.28-2.40 (s, 3H),2.20 (s, 3H), 2.18 (s, 3H). m/z (ES+) (M+H)+=593.

Example 126,N-(3-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.200 g, 1.23 mmol) wasdissolved in DMA (3 mL) and put under an inert atmosphere. DIPEA (0.537mL, 3.09 mmol) and HATU (0.469 g, 1.23 mmol) were added and the reactionstirred for 15 minutes. Compound 2 (0.278 g, 1.03 mmol) was added andthe reaction was stirred at ambient temperature for approximately 24hours then at 40° C. overnight. The reaction was cooled, diluted withwater and the solids filtered. The solids were dissolved in DMF andpurified by preparative HPLC. Fractions containing the desired compoundwere evaporated to dryness to afford the desired material as a solid(0.163 g, 38%). ¹H NMR (400 MHz, DMSO) δ 11.93 (s, 1H), 10.29 (s, 1H),10.08 (s, 1H), 8.84 (d, J=2.1 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.32 (t,J=2.0, 2.0 Hz, 1H), 7.71-7.38 (m, 5H), 7.30 (t, J=8.1, 8.1 Hz, 1H), 6.99(d, J=8.4 Hz, 1H), 6.61 (d, J=3.5 Hz, 1H), 4.38-4.25 (m, 4H). m/z (ES+)(M+H)+=415.

Preparation of Compound 133,N-(4-Fluoro-3-nitrophenyl)-2,3-dihydro-1,4-benzodioxine-7-carboxamide

2,3-Dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (2.77 g, 15.37 mmol)was dissolved in DMA (25 mL) and DIPEA (6.69 mL, 38.43 mmol) and HATU(5.85 g, 15.37 mmol) added under an inert atmosphere. The reaction wasallowed to stir for 15 minutes then 4-fluoro-3-nitroaniline (2.000 g,12.81 mmol) was added and the reaction stirred at ambient temperatureovernight. The reaction was heated for a further 16 hours at 40° C. thenconcentrated in vacuo and water added. The solids were isolated byfiltration, washed with water and dried in a vacuum oven. The solidswere stirred in EtOAc for an hour and then filtered. The filtrate wasevaporated down and the solids were triturated with DCM then filtered.The collected solids were combined to afford the desired material as acream solid (3.50 g, 86%). ¹H NMR (400 MHz, DMSO, 30° C.) d 4.29-4.36(4H, m), 7.02 (1H, d), 7.50-7.63 (3H, m), 8.15 (1H, ddd), 8.69 (1H, dd),10.46 (1H, s). m/z (ES+) (M+H)+=319.

Preparation of Compound 134,N-(3-Amino-4-fluorophenyl)-2,3-dihydro-1,4-benzodioxine-7-carboxamide

A mixture of Compound 133 (2.96 g, 9.31 mmol) and palladium (10% oncharcoal, 0.495 g) in ethanol (25 mL)/EtOAc (25 mL)/THF (25 mL) werestirred under an atmosphere of hydrogen at ambient temperatureovernight. The reaction mixture was filtered through celite and thecelite was washed with THF. The filtrate and washings were combined andevaporated to afford the desired material as an off white solid (2.70 g,101%). ¹H NMR (400 MHz, DMSO, 30° C.) d 4.27-4.35 (4H, m), 5.10 (2H, d),6.84 (1H, ddd), 6.92 (1H, dd), 6.95-6.98 (1H, m), 7.26-7.32 (1H, m),7.48 (2H, dt), 9.80 (1H, s). m/z (ES+) (M+H)+=289.

Example 127,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.200 g, 1.23 mmol) wasdissolved in DMA (3 mL) and put under nitrogen. DIPEA (0.537 mL, 3.09mmol) and HATU (0.469 g, 1.23 mmol) were added and the reaction stirredfor 15 minutes. Compound 134 (0.296 g, 1.03 mmol) was added and thereaction was stirred at ambient temperature for approximately 24 hoursthen at 40° C. overnight. The reaction was cooled, diluted with waterand the solids filtered. The solids were dissolved in DMF and purifiedby preparative HPLC. Fractions containing the desired compound wereevaporated to dryness to afford the desired material as a solid (0.074g, 17%). ¹H NMR (400 MHz, DMSO) δ 10.00 (s, 1H), 8.83 (d, J=2.1 Hz, 1H),8.56 (d, J=2.1 Hz, 1H), 8.22 (d, J=2.6 Hz, 1H), 7.69-7.57 (m, 2H),7.57-7.45 (m, 2H), 7.07 (d, J=9.0 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.61(d, J=3.5 Hz, 1H), 4.23-4.37 (m, 4H). (2 exchangeable protons notobserved) m/z (ES+) (M+H)+=433.

Example 128—Preparation ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-methylquinoline-6-carboxamide

This was prepared as for Example 127, substituting2-Methylquinoline-6-carboxylic acid for1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid. ¹H NMR (400 MHz, DMSO) δ10.33 (s, 1H), 10.15 (s, 1H), 8.61 (d, J=1.93 Hz, 1H), 8.41 (d, J=8.52Hz, 1H), 8.23 (dd, J=2.04, 8.77 Hz, 1H), 8.18-8.08 (m, 1H), 8.03 (d,J=8.79 Hz, 1H), 7.73-7.59 (m, 1H), 7.57-7.48 (m, 3H), 7.34-7.19 (m, 1H),6.99 (d, J=8.38 Hz, 1H), 4.39-4.20 (m, 4H), 2.71 (s, 3H). m/z (ES+)(M+H)+=458.

Preparation of Compound 135, tert-butylN-[3-amino-4-(trifluoromethyl)phenyl]carbamate

tert-Butyl 3-nitro-4-(trifluoromethyl)phenylcarbamate (680 mg, 2.22mmol) and palladium (59.1 mg, 0.56 mmol) in ethanol (7 mL) was stirredat ambient temperature under an atmosphere of hydrogen for 16 hours. Thereaction mixture was filtered through a pad of celite and concentratedin vacuo to afford the desired material as a yellow oil whichcrystallised on standing (613 mg, 100%). ¹H NMR (400 MHz, DMSO, 30° C.)1.47 (9H, s), 5.42 (2H, s), 6.63 (1H, d), 7.06-7.25 (2H, m), 9.36 (1H,s).

Preparation of Compound 136, tert-butylN-[3-[(2-methylquinoline-6-carbonyl)amino]-4-(trifluoromethyl)phenyl]carbamate

Phosphorus oxychloride (0.454 mL, 4.87 mmol) was added dropwise to astirred suspension of Compound 135 (0.612 g, 2.22 mmol),6-carboxy-2-methylquinolinium chloride (0.495 g, 2.22 mmol) and DIPEA(1.929 mL, 11.08 mmol) in DCM (5 mL) at 0° C. The reaction mixture wasthen warmed to ambient temperature and stirred for 30 minutes. Asaturated solution of sodium bicarbonate (50 mL) was added carefullyover 30 mins then the mixture was extracted with DCM (2×50 mL). Thecombined organics were washed with brine, passed through a phaseseparating cartridge and concentrated in vacuo to give a yellow solid.The crude product was purified by flash silica chromatography, elutiongradient 0 to 4% MeOH in DCM, to afford the desired material as a whitesolid (0.431 g, 44%). ¹H NMR (400 MHz, DMSO, 30° C.) 1.50 (9H, s), 3.29(3H, s), 7.49-7.60 (2H, m), 7.65-7.78 (2H, m), 8.04 (1H, d), 8.20 (1H,dt), 8.41 (1H, d), 8.56 (1H, d), 9.86 (1H, s), 10.27 (1H, s).

Preparation of Compound 137,N-[5-Amino-2-(trifluoromethyl)phenyl]-2-methylquinoline-6-carboxamide

TFA (2.5 mL) was added to a stirred solution of Compound 136 (426 mg,0.96 mmol) in DCM (5 mL) and the reaction stirred at ambient temperaturefor 1 hour. The crude product was purified by ion exchangechromatography, using an SCX column, and the desired product eluted fromthe column using 7M NH₃/MeOH. The pure fractions were evaporated todryness to afford the desired material as a yellow solid (330 mg, 100%).¹H NMR (400 MHz, DMSO, 30° C.) 2.70 (3H, d), 5.89 (2H, s), 6.60 (1H,dd), 6.68 (1H, d), 7.38 (1H, d), 7.44-7.58 (1H, m), 7.96-8.04 (1H, m),8.12-8.22 (1H, m), 8.39 (1H, t), 8.53 (1H, dd), 9.98 (1H, s). m/z (ES+)(M+H)+=346.21.

Example 129,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(trifluoromethyl)phenyl)-2-methylquinoline-6-carboxamide

Phosphorus oxychloride (0.196 mL, 2.10 mmol) was added dropwise to astirred suspension of 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid(172 mg, 0.96 mmol), Compound 137 (330 mg, 0.96 mmol) and DIPEA (0.832mL, 4.78 mmol) in DCM (5 mL) at 0° C. The reaction mixture was allowedto come to ambient temperature and stirred for 4 days. A saturatedaqueous solution of sodium bicarbonate (50 mL) was added carefully over30 mins then the mixture was extracted with DCM (2×50 mL). The combinedorganics were washed with brine, passed through a phase separatingcartridge and concentrated in vacuo to give a yellow solid. The crudeproduct was purified by preparative HPLC. Fractions containing thedesired compound were evaporated to dryness to afford the desiredmaterial as a white solid (26 mg, 5%). ¹H NMR (400 MHz, DMSO) δ 10.42(s, 1H), 10.32 (s, 1H), 8.56 (d, J=1.9 Hz, 1H), 8.41 (d, J=8.5 Hz, 1H),8.21 (dd, J=2.0, 8.8 Hz, 1H), 8.09-8.01 (m, 2H), 7.97 (d, J=8.7 Hz, 1H),7.78 (d, J=8.9 Hz, 1H), 7.64-7.44 (m, 3H), 7.01 (d, J=8.4 Hz, 1H),4.39-4.24 (m, 4H), 2.71 (s, 3H). m/z (ES+) (M+H)+=508.4.

Preparation of Compound 138, tert-butylN-(4-methyl-3-nitrophenyl)carbamate

Di-tert-butyl dicarbonate (25.9 g, 118.90 mmol) in THF (50 mL) was addeddropwise to 4-methyl-3-nitroaniline (18.09 g, 118.90 mmol) intetrahydrofuran (70 mL) at 65° C. over a period of 20 minutes under air.The resulting solution was stirred at 65° C. for 16 hours. The solventswere removed in vacuo to give a brown oil which was dissolved in 200 mLof 20% Ethyl acetate/isohexane and 80 g silica gel added. The mixturewas stirred for 15 mins then the silica filtered off and washed with 500mL of 20% Ethyl acetate/isohexane and the filtrates combined andconcentrated. The crude product was purified by flash silicachromatography, elution gradient 0 to 20% EtOAc in isohexane to affordthe desired material as a yellow solid (26.7 g, 89%). ¹H NMR (400 MHz,CDCl3, 30° C.) d 1.52 (9H, s), 2.52 (3H, s), 6.61 (1H, s), 7.23 (1H, d),7.48 (1H, dt), 8.03 (1H, d). m/z (ES+) (M−H)−=251.47.

Preparation of Compound 139, tert-butylN-(3-amino-4-methylphenyl)carbamate

Compound 138 (30.5 g, 120.90 mmol) and palladium on carbon (5% JMType87L, 6.1 g) in MeOH (300 mL) were stirred under an atmosphere ofhydrogen at 5 bar and 25° C. for 3 hours. The catalyst was filtered offthrough a pad of celite, washed with methanol and filtrate concentratedin vacuo to give an orange oil. The crude product was purified by flashsilica chromatography, elution gradient 0 to 2% MeOH in DCM, to affordthe desired material as a white solid (22.60 g, 96%). ¹H NMR (400 MHz,DMSO, 30° C.) d 1.45 (9H, s), 1.96 (3H, s), 6.49 (1H, dd), 6.74 (1H, d),6.82 (1H, d), 8.85 (1H, s). m/z (ES+) (M+H)+=223.5.

Preparation of Compound 140, tert-butylN-[4-methyl-3-[(2-methylquinoline-6-carbonyl)amino]phenyl]carbamate

HATU (20.12 g, 52.91 mmol) was added portionwise to Compound 139 (9.80g, 44.09 mmol), 2-methylquinoline-6-carboxylic acid (8.67 g, 46.29 mmol)and DIPEA (23.04 mL, 132.26 mmol) in DMA (197 mL) at ambient temperatureunder an inert atmosphere and the resulting solution stirred overnight.The reaction mixture was concentrated, diluted with DCM (50 mL), andwashed sequentially with a saturated solution of sodium bicarbonate (50mL), saturated brine (50 mL), and water (50 mL). The organic layer wasdried over MgSO₄, filtered and evaporated to afford a dark solid. Thecrude product was purified by flash silica chromatography, elutiongradient 0 to 5% MeOH in DCM, to afford the desired material as an offwhite solid (8.25 g, 48%). ¹H NMR (400 MHz, DMSO, 30° C.) d 1.37 (9H,d), 2.18 (3H, s), 2.61-2.85 (3H, m), 7.14 (1H, d), 7.23 (1H, dd), 7.52(1H, d), 7.56 (1H, d), 8.02 (1H, d), 8.22 (1H, dd), 8.39 (1H, d), 8.58(1H, d), 9.28 (1H, s), 10.04 (1H, s). m/z (ES+) (M+H)+=392.56.

Preparation of Compound 141,N-(5-amino-2-methylphenyl)-2-methylquinoline-6-carboxamide

TFA (80 mL) was added to Compound 140 (8.25 g, 21.07 mmol) in DCM (2 mL)at ambient and the reaction stirred for 1 hour. The crude product waspurified by ion exchange chromatography, using an SCX column, and thedesired product eluted from the column using 7 M NH₃/MeOH. The purefractions were evaporated to dryness and the residue triturated indiethyl ether, filtered and dried to afford the desired material as asolid (5.42 g, 88%). ¹H NMR (400 MHz, DMSO, 21° C.) d 2.09 (3H, s),2.65-2.74 (3H, m), 4.94 (2H, s), 6.41 (1H, dd), 6.64 (1H, d), 6.91 (1H,d), 7.51 (1H, d), 8.00 (1H, d), 8.21 (1H, dd), 8.39 (1H, d), 8.56 (1H,d), 9.86 (1H, s). m/z (ES+) (M+H)+=292.51.

Example 130,N-(5-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methylquinoline-6-carboxamide

Oxalyl chloride (0.065 mL, 0.76 mmol) was added dropwise to6-fluoro-2,3-dihydro-1,4-benzodioxine-7-carboxylic acid (100 mg, 0.50mmol), and DMF (a couple of drops) in DCM (10 mL) at ambient temperaturefor 4 hours. The reaction mixture was evaporated to afford6-fluoro-2,3-dihydro-1,4-benzodioxine-7-carbonyl chloride as acolourless gum (110 mg) which was used without further purification. Asolution of 6-fluoro-2,3-dihydro-1,4-benzodioxine-7-carbonyl chloride(108 mg, 0.5 mmol) in DCM (10 mL) was added dropwise to a stirredsuspension of Compound 141 (146 mg, 0.50 mmol) and pyridine (0.040 mL,0.50 mmol) in DCM (30 mL) and the resulting mixture stirred at ambienttemperature for 3 hours. The reaction mixture was evaporated to drynessand redissolved in a mixture of DMSO/MeCN/H₂O (7:2:1.4 mL) and purifiedby preparative HPLC. Fractions containing the desired compound wereevaporated to dryness to afford the desired material as a yellow solid(50.0 mg, 21%). ¹H NMR (DMSO, 400 MHz) δ 10.15 (1H, s), 10.11 (1H, s),8.61 (1H, d, J=1.9 Hz), 8.41 (1H, d, J=8.4 Hz), 8.25 (1H, dd, J=8.8, 2.0Hz), 8.03 (1H, d, J=8.8 Hz), 7.83 (1H, d, J=2.0 Hz), 7.47-7.57 (2H, m),7.25 (1H, d, J=8.5 Hz), 7.17 (1H, d, J=7.0 Hz), 6.92 (1H, d, J=11.0 Hz),4.31-4.36 (2H, m), 4.21-4.3 (2H, m), 2.72 (3H, s), 2.25 (3H, s). m/z(ES+) (M+H)+=472.

Example 131—Preparation ofN-(5-(benzo[d][1,3]dioxole-5-carboxamido)-2-methylphenyl)quinoline-6-carboxamide

HATU (891 mg, 2.34 mmol) was added to 1,3-benzodioxole-5-carboxylic acid(344 mg, 2.07 mmol), N-(5-amino-2-methylphenyl)quinoline-6-carboxamide(500 mg, 1.80 mmol) and DIPEA (0.945 mL, 5.41 mmol) in DMA (15 mL) andthe mixture stirred at ambient temperature under an inert atmosphere for3 days. The reaction mixture was diluted with EtOAc (300 mL), and washedwith water (2×150 mL). The organic layer was dried over Na₂SO₄, filteredand evaporated to afford crude product. The crude product was purifiedby flash silica chromatography, elution gradient 20 to 100% EtOAc inisohexane. The pure fractions were evaporated to dryness, triturated inDCM and the solid filtered to afford the desired material as a whitesolid (290 mg, 38%). ¹H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 10.07 (s,1H), 9.03 (dd, J=1.7, 4.2 Hz, 1H), 8.68 (d, J=1.9 Hz, 1H), 8.49-8.6 (m,1H), 8.30 (dd, J=2.0, 8.8 Hz, 1H), 8.2 (d, J=8.8 Hz, 1H), 7.89 (s, 1H),7.5-7.7 (m, 4H), 7.26 (d, J=8.48 Hz, 1H), 7.06 (d, J=8.16 Hz, 1H), 6.14(s, 2H), 2.26 (s, 3H). m/z (ES+) (M+H)+=426.

Preparation of Compound 142,2-amino-4-methoxy-1,3-benzothiazole-6-carboxylic acid¹⁰

Methyl 2-amino-4-methoxy-1,3-benzothiazole-6-carboxylate (2 g) was addedto hydrogen bromide (48% in acetic acid, 50 mL) and the mixture stirredfor 1 hour. Water (˜5 mL) was added dropwise to ensure material was insolution and the material stirred at ambient temperature for 16 hoursthen heated at reflux for 5 hours. The mixture was allowed to cool andthe solid removed by filtration to give the desired material (2.37 g)which was used without further purification. ¹H NMR (300 MHz, DMSO) δ8.07 (1H, s), 7.48 (1H, s), 3.93 (3H, s).

Preparation of Compound 143,3-Methyl-4-oxo-3,4-dihydroquinazoline-6-carboxylate

4-Oxo-3,4-dihydroquinazoline-6-carboxylic acid (0.875 g, 4.60 mmol) andpotassium carbonate (3.18 g, 23.01 mmol) were suspended in dry acetone(40 mL) and dimethyl sulfate (0.873 mL, 9.20 mmol) was added. Thereaction was stirred at reflux for several hours and then allowed tocool, the suspension filtered and the filtrate concentrated in vacuo togive the desired product as a solid (0.823 g, 82%). ¹H NMR (400 MHz,DMSO) δ 8.72 (1H, d), 8.51 (1H, s), 8.30 (1H, dt), 7.78 (1H, d), 3.92(3H, s), 3.53 (3H, s). m/z (ES+) (M+H)+=219.

Preparation of Compound 144,3-methyl-4-oxo-3,4-dihydroquinazoline-6-carboxylic acid

Compound 143 (0.550 g, 2.52 mmol) and lithium hydroxide (0.302 g, 12.60mmol) were dissolved in THF (8 mL) and water (2.0 mL) then heated to 50°C. for an hour. The reaction was cooled, water was added and the pHadjusted to ˜3. DCM was added and the resultant precipitation removed byfiltration. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo to yield the desired material, ˜65% pure based onHPLC data, as a solid (0.30 g, 58%) which was used in the subsequentreaction without further purification. ¹H NMR (400 MHz, DMSO) δ12.84-11.95 (1H, m), 8.71 (1H, d), 8.50 (1H, s), 8.28 (1H, dt), 7.76(1H, dd), 3.52 (3H, s). m/z (ES+) (M+H)+=205.

Example 132,N-(5-(3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-carboxamido)-2-methylphenyl)-2-methylquinoline-6-carboxamide

HATU (0.082 g, 0.22 mmol) was added to a solution of3,4-dihydro-2H-1,5-benzodioxepin-7-carboxylic acid andN,N-diisopropylethylamine (0.075 mL, 0.43 mmol) in dry DMF (1.2 mL). Thereaction mixture was stirred for 4 min, before Compound 141 (0.050 g,0.17 mmol) was added. The reaction mixture was stirred at rt for 23 h,diluted with water and the resulting precipitate was isolated byfiltration, washed with water and dried. The crude material was purifiedby silica gel column chromatography using a gradient of 1 to 5% MeOH inDCM to afford the title compound (55 mg, 68%) as a white solid. ¹H NMR(500 MHz, DMSO) δ 10.13 (s, 1H), 10.13 (s, 1H), 8.61 (d, J=2.0 Hz, 1H),8.41 (d, J=8.5 Hz, 1H), 8.24 (dd, J=8.8, 2.0 Hz, 1H), 8.03 (d, J=8.8 Hz,1H), 7.88 (d, J=2.2 Hz, 1H), 7.63 (d, J=2.2 Hz, 1H), 7.61-7.57 (m, 2H),7.53 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H),4.24-4.18 (m, 4H), 2.71 (s, 3H), 2.24 (s, 3H), 2.15 (p, J=5.6 Hz, 2H).HRMS (ESI⁺): calcd for C₂₈H₂₆N₃O₄ (M+H)⁺, 468.1918; found 468.1918.

Example 133,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-ethylphenyl)quinoline-6-carboxamide

A solution of B(Et)₃ (60 μL, 0.18 mmol, 3.0 eq) in dry 1,4 dioxane (0.12ml) was added to a mixture of Example 138 (30 mg, 0.060 mmol, 1.0 eq),Cs₂CO₃ (20 mg, 0.060 mmol, 1.0 eq) and Pd(dppf)C₁₂ (0.3 mg, 0.0004mmol). The mixture was stirred under argon at 70° C. for 3 h. Aftercooling to r.t., the mixture was dropped into water and extracted withDCM. The organic phase was dried over Na₂SO₄ and concentrated. The crudewas purified by preparative TLC (DCM/MeOH 97:3) to afford the titlecompound (8 mg). ¹H NMR (500 MHz, DMSO) δ 10.19 (s, 1H), 10.09 (s, 1H),9.04-9.00 (m, 1H), 8.66 (s, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.29 (d, J=8.8Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.83 (s, 1H), 7.67-7.63 (m, 2H), 7.54(d, J=2.3 Hz, 1H), 7.51 (dd, J=8.5, 2.2 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H),6.98 (d, J=8.4 Hz, 1H), 4.34-4.28 (m, 4H), 2.63 (q, J=7.7 Hz, 2H), 1.15(t, J=7.5 Hz, 3H).

HRMS: calcd for C₂₇H₂₄N₃O₄ (M+H)⁺, 454.1761; found 454.1755.

Preparation of Compound 145,N-(2-methyl-5-nitrophenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide

Oxalyl chloride (10.7 g, 84.3 mmol) was added to a suspension ofCompound 70 (2.26 g, 7.00 mmol) in DCM (12 mL) and DMF (0.014 mL) andthe reaction mixture was stirred at rt for 3 days, concentrated,dissolved in DCM (15 mL) and added dropwise to a solution of2-methyl-5-nitroaniline (1.07 g, 7.03 mmol) and pyridine (2.3 mL) in DCM(10 mL). The reaction mixture was stirred at rt for 6 h, and thenconcentrated. The residue was suspended in MeOH, and the solid isolatedby filtration. The crude material was purified by silica gel columnchromatography using 4% MeOH in DCM and then 6% 2 M NH₃/MeOH in DCM toafford the title compound (1.20 g, 41%) as a white solid. ¹H NMR (500MHz, DMSO) δ 10.30 (s, 1H), 8.59 (d, J=2.1 Hz, 1H), 8.43-8.37 (m, 2H),8.23 (dd, J=8.7, 2.1 Hz, 1H), 8.05 (dd, J=8.5, 2.5 Hz, 1H), 7.88 (d,J=8.7 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 4.57 (t,J=5.8 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.56 (br s, 4H), 2.43 (s, 3H),1.72-1.67 (m, 4H). HRMS: calcd for C₂₃H₂₅N₄O₄ (M+H)⁺, 421.1870; found421.1864.

Preparation of Compound 146,N-(5-amino-2-methylphenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide

A suspension of Compound 145 (85 mg, 2.0 mmol) and 10% Pd/C (84 mg) inEtOAc (12 ml), EtOH (12 ml) and DCM (4 ml) was stirred under anatmosphere of hydrogen gas at rt for 3.5 h, filtered through a celitepad and concentrated under vacuum to afford the title compound as ayellow solid that was used without any further purification. ¹H NMR (500MHz, CDCl₃) δ 8.28 (d, J=2.1 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 8.04 (dd,J=8.7, 2.1 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.75 (s, 1H), 7.59-7.53 (m,1H), 7.03 (d, J=8.9 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.47 (dd, J=8.1,2.5 Hz, 1H), 4.70 (t, J=5.8 Hz, 2H), 3.67 (br s, 2H), 3.04 (t, J=5.8 Hz,2H), 2.76 (br s, 4H), 1.90-1.85 (m, 4H). HRMS: calcd for C₂₃H₂₆N₄O₂(M+H)⁺, 391.2129; found 391.2122.

Example 134,N-(4-methyl-3-(2-(2-(Pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamido)phenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxamide

To a solution of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxylicacid (0.015 g, 0.085 mmol) and DIEA (0.030 mL, 0.17 mmol) in dry DMF(0.4 mL) was added HATU (0.037 g, 0.096 mmol) and the reaction mixturewas stirred at rt for 5 min before Compound 146 (0.030 g, 0.077 mmol)was added. The reaction mixture was stirred at rt overnight, dilutedwith water and the resulting solid was isolated by filtration, washedwith water and dried. The crude material was purified by silica gelcolumn chromatography using a gradient of 5 to 15% MeOH in DCM to affordthe title compound (0.013 g, 30%) as a white solid. ¹H NMR (500 MHz,DMSO) δ 10.23 (s, 1H), 10.09 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.40 (d,J=8.8 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 8.23 (dd, J=8.8, 2.1 Hz, 1H),7.90-7.85 (m, 2H), 7.84 (d, J=2.1 Hz, 1H), 7.57 (dd, J=8.2, 2.2 Hz, 1H),7.26 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 4.62 (t, J=5.8 Hz, 2H),4.51-4.47 (m, 2H), 4.34-4.29 (m, 2H), 3.09 (br s, 2H), 2.78 (br s, 4H),2.25 (s, 3H), 1.77 (br s, 4H). HRMS calcd for C₃₁H₃₂N₅O₅ (M+H)⁺,554.2398; found 554.2380.

Example 135,N-(4-methyl-3-(2-methylquinoline-6-carboxamido)phenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxamide

This was prepared as for Example 134, substituting Compound 141 forCompound 146. ¹H NMR (500 MHz, DMSO) δ 10.23 (s, 1H), 10.14 (s, 1H),8.61 (d, J=2.0 Hz, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H),8.24 (dd, J=8.7, 2.0 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.87 (d, J=2.2 Hz,1H), 7.84 (d, J=2.1 Hz, 1H), 7.59 (dd, J=8.2, 2.2 Hz, 1H), 7.53 (d,J=8.4 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 4.52-4.45 (m, 2H), 4.35-4.29 (m,2H), 2.71 (s, 3H), 2.25 (s, 3H). HRMS: calcd for C₃₁H₃₃N₅O₅ (M+H)⁺,455.1714; found 455.1713.

Preparation of Compound 147, ethyl 2-formylquinoline-6-carboxylate

To a stirring suspension of selenium dioxide (359 mg, 3.23 mmol) in1,4-dioxane (4.5 mL) under argon was added ethyl2-methylquinoline-6-carboxylate (633 mg, 2.94 mmol). The reactionmixture was heated to 80° C. and left to stir for 23 h. Further seleniumdioxide (80 mg, 0.72 mmol, 0.24 eq.) was added and the reaction heatedfor 3 h, the reaction mixture was allowed to cool and was filteredthrough celite (eluting with DCM). The filtrate was concentrated invacuo to afford the crude title compound as an orange solid (674 mg,quantitative). This material was used directly in the next reactionwithout further purification. ¹H NMR (500 MHz, Chloroform-d) δ 10.26 (d,J=0.8 Hz, 1H), 8.68 (d, J=1.8 Hz, 1H), 8.48-8.41 (m, 2H), 8.32 (d, J=8.8Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 4.55-4.45 (m, 4H), 1.51-1.46 (m, 3H).

Preparation of Compound 148, ethyl2-(hydroxymethyl)quinoline-6-carboxylate

To a stirring suspension of Compound 147 (213 mg, 0.929 mmol) in ethanol(6.5 mL) and water (3.25 mL) at 0° C. was added sodium borohydride (176mg, 4.65 mmol) and the reaction left to stir at 0° C. for 2.5 h. Thereaction mixture was diluted with water (30 ml) and extracted with EtOAc(2×30 ml)—brine was added to clear. The combined organic layer waswashed with brine (30 ml), dried (MgSO₄) and concentrated in vacuo. Thecrude material was purified by biotage chromatography using a gradientof 5 to 40% EtOAc in DCM to afford the title compound as a yellow solid(132 mg, 61%). ¹H NMR (500 MHz, Chloroform-d) δ 8.62 (d, J=1.9 Hz, 1H),8.35 (dd, J=8.8, 1.9 Hz, 1H), 8.27 (d, J=8.3 Hz, 1H), 8.14 (d, J=8.8 Hz,1H), 7.38 (d, J=8.5 Hz, 1H), 4.98 (s, 1H), 4.49 (q, J=7.1 Hz, 2H), 4.39(s, 1H), 1.48 (t, J=7.1 Hz, 3H). HRMS (ESI⁺): calcd for C₁₃H₁₄NO₃(M+H)⁺, 232.0974; found 232.0972.

Preparation of Compound 149, ethyl2-(((tert-butyldimethylsilyl)oxy)methyl)quinoline-6-carboxylate

To a solution of Compound 148 (75 mg, 0.324 mmol) in anhydrous DCM (3.0mL) under argon was added imidazole (33.1 mg, 0.486 mmol), followed bytert-butyldimethylsilyl chloride (56.2 mg, 0.373 mmol). The reaction wasstirred at room temperature for 4 days, then diluted with DCM (10 ml)and washed with water (1×10 ml), 0.25 M HCl aq. (1×10 ml), brine (1×10ml), dried (Na₂SO₄), concentrated and dried in vacuo to afford the titlecompound as a yellow oil (103 mg, 92%). ¹H NMR (500 MHz, Chloroform-d) δ8.60 (d, J=1.8 Hz, 1H), 8.31 (dd, J=8.8, 2.1 Hz, 2H), 8.05 (d, J=8.8 Hz,1H), 7.79 (d, J=8.5 Hz, 1H), 5.03 (s, 2H), 4.47 (q, J=7.2 Hz, 2H), 1.47(t, J=7.1 Hz, 3H), 1.00 (s, 9H), 0.17 (s, 6H). HRMS (ESI⁺): calcd forC₁₉H₂₇NO₃Si (M+H)⁺, 347.1859; found 347.1853.

Preparation of Compound 150,2-(((tert-butyldimethylsilyl)oxy)methyl)quinoline-6-carboxylic acid

To a stirring solution of Compound 149 (39 mg, 0.113 mmol) in THF (0.9mL) and methanol (0.3 mL) was added 2M NaOH aq. (0.113 mL, 0.226 mmol).The reaction was left to stir at room temperature for 2 days. Further 2MNaOH aq. (0.113 mL, 0.226 mmol) was added and the reaction was heated to50° C. for 5 h. Further 2M NaOH aq. (0.113 mL, 0.226 mmol) was added andthe reaction left to stir at room temperature for 18.5 h. The reactionmixture was diluted with water (10 ml) and the aqueous layer acidifiedby the addition of 1M HCl aq. (to ˜pH 3). The aqueous layer wasextracted with EtOAc (2×20 ml) and the combined organic layer dried(MgSO₄). LCMS (ESI⁺): showed a 2.7:1 mixture of2-(hydroxymethyl)quinoline-6-carboxylic acid (−TBDMS) and the titlecompound. This mixture was used directly in the next reaction withoutfurther purification. HRMS (ESI⁺): calcd for C₁₇H₂₃NO₃Si (M+H)⁺,318.1525; found 318.1518.

Preparation of Compound 151,2-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide

To a stirring solution of crude Compound 150 (36 mg, 0.113 mmol,theoretical yield used) in DMF (1.2 mL) at room temperature under argonwas added DIEA (0.043 mL, 0.249 mmol), followed by HATU (56.1 mg, 0.147mmol). The reaction mixture was allowed to stir for 5 min beforeCompound 2 (38.7 mg, 0.136 mmol) was added. The mixture was allowed tostir at room temperature for 16 h then it was diluted with water (10 ml)and extracted with EtOAc (2×25 ml)—brine was added to clear. Thecombined organic layer was washed with brine (25 ml), dried (Na₂SO₄) andconcentrated in vacuo. The crude residue was purified by biotagechromatography using a gradient of 10 to 80% EtOAc in DCM to afford thetitle compound as an off-white solid (9.5 mg, 44% based on percentage ofstarting material in crude mixture).

Preparation of Compound 152,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(hydroxymethyl)quinoline-6-carboxamide

To a stirring solution of Compound 151 (9.5 mg, 0.016 mmol) in THF (0.5mL) at room temperature under argon was slowly added TBAF (1M in THF,0.024 mL, 0.024 mmol). The reaction mixture was allowed to stir for 3 h.The reaction mixture was diluted with water (20 ml) and the aqueouslayer extracted with EtOAc (2×20 ml). The combined organic layer waswashed with brine (10 ml), dried Na₂SO₄ and concentrated in vacuo toafford the crude product as a cream solid. This material was purified bycolumn chromatography using a gradient of 20 to 33% EtOAc/DCM, then 10%MeOH/DCM to afford the title compound as a pale yellow solid (4.4 mg,58%). ¹H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 10.10 (s, 1H), 8.65 (d,J=1.8 Hz, 1H), 8.54 (d, J=8.5 Hz, 1H), 8.27 (dd, J=8.8, 2.0 Hz, 1H),8.07 (d, J=8.8 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H),7.60 (dd, J=8.3, 2.1 Hz, 1H), 7.55 (d, J=2.1 Hz, 1H), 7.52 (dd, J=8.4,2.2 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 4.78 (s,2H), 4.41-4.23 (m, 10H), 2.26 (s, 3H). HRMS (ESI⁺): calcd forC₂₇H₂₄NO₃O₅(M+H)⁺, 470.1710; found 470.1691.

Preparation of Compound 153, butyl 8-fluoroquinoline-6-carboxylate

To a stirring suspension of 6-bromo-8-fluoroquinoline (72 mg, 0.319mmol), Hermann's palladacycle (14.9 mg, 0.016 mmol) andtri-t-butylphosphonium tetrafluoroborate (18.5 mg, 0.064 mmol) inbutanol (1.0 mL) was added molybdenum hexacarbonyl (168 mg, 0.637 mmol)followed by DBU 1.0M in THF (0.96 ml, 0.956 mmol). The reaction washeated to 130° C. in a microwave for 1 h. The reaction mixture wasfiltered through celite then concentrated in vacuo. The resultingresidue was dry-loaded onto silica and purified by column chromatographyusing a gradient of 10 to 20% EtOAc/petroleum ether to afford the titlecompound as a yellow solid (60 mg, 70%). ¹H NMR (500 MHz, Chloroform-d)δ 9.08 (dd, J=4.2, 1.6 Hz, 1H), 8.42 (s, 1H), 8.33 (dt, J=8.4, 1.5 Hz,1H), 8.01 (dd, J=10.9, 1.7 Hz, 1H), 7.57 (dd, J=8.4, 4.2 Hz, 1H), 4.42(t, J=6.6 Hz, 2H), 1.91-1.75 (m, 2H), 1.53 (dq, J=14.8, 7.4 Hz, 2H),1.03 (t, J=7.4 Hz, 3H). HRMS (ESI⁺): calcd for C₁₄H₁₅FNO₂ (M+H)⁺,248.1081; found 248.1080.

Preparation of Compound 154, 8-fluoroquinoline-6-carboxylic acid

To a stirring solution of Compound 153 (53 mg, 0.214 mmol) in THF (1.5mL) and MeOH (0.5 mL) was added 2M NaOH aq. (0.536 mL, 1.072 mmol) andthe reaction mixture left to stir for 16 h. The reaction mixture wasdiluted with water (20 ml) and acidified using 1 M HCl aq. (to ˜pH 3)The aqueous layer was extracted with DCM (3×15 ml) and the combinedorganic layer dried with (Na₂SO₄) then concentrated in vacuo to affordthe title compound as an orange solid (34 mg, 83%). This material wasused directly in the next reaction without further purification. ¹H NMR(500 MHz, Methanol-d4) b 8.96 (dd, J=4.2, 1.5 Hz, 1H), 8.38 (s, 3H),8.30 (d, J=8.4 Hz, 1H), 7.96 (dd, J=10.9, 1.5 Hz, 1H), 7.54 (dd, J=8.4,4.3 Hz, 3H). HRMS (ESI⁺): calcd for C₁₀H₇FNO₂ (M+H)⁺, 192.0461; found192.0462.

Example 136,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-8-fluoroquinoline-6-carboxamide

To a stirring solution of Compound 154 (30 mg, 0.157 mmol) in DMF (1.0mL) at room temperature under argon was added DIEA (0.087 mL, 0.502mmol), followed by HATU (78 mg, 0.204 mmol). The reaction mixture wasallowed to stir for 5 min before Compound 2 (53.5 mg, 0.188 mmol) wasadded. The reaction mixture was allowed to stir at room temperature for16 h. The reaction mixture was diluted with water (20 ml) and extractedwith EtOAc (3×15 ml)—brine was added to clear. The combined organiclayer was washed with brine (15 mL), dried Na₂SO₄ and concentrated invacuo. The resulting residue was purified by column chromatography usinga gradient of 5 to 25% EtOAc/DCM to afford an off-white solid (25 mg).However, this material required further purification. Therefore 15 mg ofthis material was purified by SCX chromatography eluting with MeOHfollowed by 5, then 10% 2M NH₃ in MeOH/MeOH to afford the title compoundas an off-white solid (10.8 mg, 15%). ¹H NMR (500 MHz, DMSO-d6) δ 10.23(s, 1H), 10.09 (s, 1H), 9.08 (dd, J=4.2, 1.6 Hz, 1H), 8.63 (d, J=8.4 Hz,1H), 8.55 (d, J=1.4 Hz, 1H), 8.11 (dd, J=11.5, 1.7 Hz, 1H), 7.88 (d,J=2.1 Hz, 1H), 7.76 (dd, J=8.4, 4.2 Hz, 1H), 7.59 (dd, J=8.3, 2.2 Hz,1H), 7.57-7.46 (m, 2H), 7.25 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H),4.33-4.29 (m, 4H), 2.69 (s, 2H), 2.24 (s, 3H). HRMS (ESI⁺): calcd forC₂₆H₂₁FN₃O₂(M+H)⁺, 458.1511; found 458.1505.

Preparation of Compound 155, 6-bromoquinoline-2-carbaldehyde

To a stirring suspension of selenium dioxide (412 mg, 3.71 mmol) in1,4-dioxane (5.5 mL) under argon was added 6-bromo-2-methylquinoline(750 mg, 3.38 mmol). The reaction was heated to 80° C. and left to stirfor 23 h. The reaction mixture was then filtered through celite andconcentrated in vacuo. The resulting residue was purified by columnchromatography using a gradient of 5 to 15% EtOAc/petroleum ether toafford the title compound as a pale yellow solid (551 mg, 69%). ¹H NMR(500 MHz, Chloroform-d) δ 10.22 (s, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.14(d, J=9.0 Hz, 1H), 8.10 (d, J=2.1 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.91(dd, J=9.0, 2.2 Hz, 1H). HRMS (ESI⁺): calcd for C₁₀H₇ ⁷⁹BrNO (M+H)⁺,235.9711; found 235.9704.

Preparation of Compound 156, (6-bromoquinolin-2-yl)methanol

To a stirring suspension of Compound 155 (1.36 g, 5.76 mmol) in ethanol(41 mL) and water (20.5 mL) at 0° C. was added sodium borohydride (1.090g, 28.8 mmol) and the reaction left to stir at 0° C. for 18 h. Thesolvents were removed in vacuo and the resulting residue diluted withwater (30 ml) and extracted with EtOAc (3×20 ml). The combined organiclayer as washed with brine (20 ml), dried (MgSO₄) and concentrated invacuo to afford the title product as a yellow solid (1.27 g, 93%). ¹HNMR (500 MHz, Methanol-d4) δ 7.35 (d, J=8.5 Hz, 1H), 7.21 (d, J=2.0 Hz,1H), 7.10 (d, J=9.0 Hz, 1H), 6.99 (dd, J=9.0, 2.1 Hz, 1H), 6.80 (d,J=8.5 Hz, 1H), 6.60 (s, 0.5H, OH), 4.07 (s, 2H). HRMS (ESI⁺): calcd forC₁₀H₉ ⁷⁹BrNO (M+H)⁺, 237.9868; found 237.9865.

Preparation of Compound 157, 6-bromo-2-(methoxymethyl)quinoline

To a stirring suspension of sodium hydride (101 mg, 2.52 mmol) in DMF(20 mL) at 0° C. under argon was slowly added Compound 156 (500 mg,2.100 mmol) portion-wise. The reaction mixture was allowed to stir at 0°C. for 0.5 h before the addition of methyl iodide (0.314 mL, 5.04 mmol).The reaction was allowed to warm gradually to room temperature andallowed to stir for 19 h. The reaction mixture was then poured intowater (100 ml) and extracted with EtOAc (3×75 ml)—brine was added toclear. The combined organic layer was washed with brine (75 ml), dried(MgSO₄) and concentrated in vacuo (last traces of DMF were removed byco-evaporation with heptane) to afford a yellow solid. The crudematerial was purified by biotage chromatography using a gradient of 5 to80% EtOAc/DCM to afford the title compound as a pale yellow solid (451mg, 85%). ¹H NMR (500 MHz, Chloroform-d) δ 8.11 (d, J=8.5 Hz, 1H), 8.00(d, J=2.2 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.80 (dd, J=9.0, 2.2 Hz, 1H),7.62 (d, J=8.5 Hz, 1H), 4.76 (s, 2H), 3.54 (s, 3H). HRMS (ESI⁺): calcdfor C₁₁H₁₁ ⁷⁹BrNO (M+H)⁺, 252.0024; found 252.0016.

Preparation of Compound 158, 2-(trimethylsilyl)ethyl2-(methoxymethyl)quinoline-6-carboxylate

To a stirring suspension of Compound 157 (173 mg, 0.686 mmol), Hermann'spalladacycle (32.2 mg, 0.034 mmol) and tri-t-butylphosphoniumtetrafluoroborate (39.8 mg, 0.137 mmol) in 2-(trimethylsilyl)-ethanol(3.0 mL) was added molybdenum hexacarbonyl (362 mg, 1.372 mmol) followedby DBU (1.0 M in THF, 2.06 ml, 2.06 mmol). The reaction mixture washeated to 130° C. in a microwave for 1 h. The reaction mixture wasfiltered through celite then concentrated in vacuo. The resultingresidue was dry-loaded onto silica and purified by column chromatographyusing a gradient of 10 to 20% EtOAc/petroleum ether to afford the titlecompound as a yellow solid (60 mg, 70%). ¹H NMR (500 MHz, Chloroform-d)δ 8.59 (d, J=1.8 Hz, 1H), 8.35-8.27 (m, 2H), 8.13 (d, J=8.5 Hz, 1H),7.67 (d, J=8.5 Hz, 1H), 4.81 (s, 2H), 4.64-4.36 (m, 2H), 3.55 (s, 3H),1.59 (s, OH), 1.27-1.11 (m, 2H), 0.13 (s, 9H). HRMS (ESI⁺): calcd forC₁₇H₂₄NO₃Si (M+H)⁺, 318.1520; found 318.1530.

Preparation of Compound 159, 2-(methoxymethyl)quinoline-6-carboxylicacid

To a stirring solution of Compound 158 (213 mg, 0.671 mmol) in THF (5.0mL) at room temperature under argon was slowly added TBAF 1.0M in THF(1.006 mL, 1.006 mmol) the reaction mixture was allowed to stir for 5 h.Water (10 ml) was added and the reaction mixture concentrated to removeTHE. The aqueous layer was then acidified (to ˜pH 3) using 1M HCl aq.and extracted with EtOAc (3×15 ml)—brine was added to clear. Thecombined organic layer was washed with brine (10 ml), dried (Na₂SO₄) andconcentrated in vacuo to afford the crude product as a pale yellowsolid. This material was used directly in the next reaction withoutfurther purification.

Example 137,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(methoxymethyl)quinoline-6-carboxamide

To a stirring solution of crude Compound 159 (148 mg, 0.477 mmol) andDIEA (0.249 mL, 1.431 mmol) in DMF (4 mL) under argon was added HATU(218 mg, 0.572 mmol). The reaction was allowed to stir for 3 min beforethe addition of Compound 2 (129 mg, 0.453 mmol). The reaction mixturewas allowed to stir at room temperature for 16 h. The reaction wasdiluted with water, the resulting precipitate isolated by filtration andwashed with water. The pale green precipitate obtained was purified bybiotage chromatography using a gradient of 12 to 100% EtOAc/DCM toafford the title compound as a cream solid (114 mg, 49%). ¹H NMR (500MHz, DMSO-d6) δ 10.17 (s, 1H), 10.08 (s, 1H), 8.66 (d, J=1.9 Hz, 1H),8.55 (d, J=8.5 Hz, 1H), 8.28 (dd, J=8.8, 2.0 Hz, 1H), 8.09 (d, J=8.8 Hz,1H), 7.88 (d, J=2.1 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.59 (dd, J=8.3,2.2 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.51 (dd, J=8.4, 2.2 Hz, 1H), 7.25(d, J=8.5 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.72 (s, 2H), 4.37-4.19 (m,4H), 3.43 (s, 3H), 2.25 (s, 3H). HRMS (ESI⁺): calcd for C₂₈H₂₆NO₅(M+H)⁺, 484.1867; found 484.1861.

Preparation of Compound 160,N-(4-bromo-3-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

Oxalyl chloride (0.282 mL, 3.33 mmol) was added drop-wise to a solutionof 1,4-benzodioxane-6-carboxylic acid (500 mg, 2.78 mmol) and DMF (5.37μL, 0.069 mmol) in dry DCM (7 mL). The reaction was allowed to stir atroom temperature for 2 h before the reaction mixture was concentrated,anhydrous DCM (7 mL) was added and concentrated again. The resultingresidue was re-dissolved in anhydrous DCM (3+3+1 mL) and added drop-wiseto a solution of 4-bromo-3-nitroaniline (602 mg, 2.78 mmol) and pyridine(0.449 mL, 5.55 mmol) in dry DCM (7 mL). The reaction was left to stirat room temperature for 18 h. The reaction mixture was concentrated andthe resulting solid suspended in MeOH, diluted with water and thenisolated by filtration. The solid was washed with water to afford thetitle compound as a pale yellow solid (1.01 g, 96%). ¹H NMR (500 MHz,DMSO-d6) δ 10.54 (s, 1H), 8.55 (d, J=2.5 Hz, 1H), 7.97 (dd, J=8.8, 2.5Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.55 (d, J=2.1 Hz, 1H), 7.52 (dd,J=8.5, 2.2 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 4.40-4.19 (m, 4H). HRMS(ESI⁺): calcd for C₁₅H₁₂ ⁷⁹BrN₂O₅(M+H)⁺, 378.9930; found 378.9920.

Preparation of Compound 161,N-(3-amino-4-bromophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

To a stirring solution of Compound 160 (750 mg, 1.978 mmol) in ethanol(12 mL) and water (4.0 mL) was added iron powder (773 mg, 13.85 mmol)followed by ammonium chloride (741 mg, 13.85 mmol). The reaction mixturewas heated to reflux for 23 h, then filtered through celite (elutingwith EtOH/EtOAc) and the solvents removed in vacuo. The resultingresidue was partitioned between water (50 mL) and EtOAc (50 mL). Theorganic layer was washed with sat. NaHCO₃ aq. (50 mL), water (50 mL),brine (30 mL) and dried (Na₂SO₄), then concentrated in vacuo to affordthe crude product as a beige solid (575 mg, 83%). ¹H NMR (500 MHz,DMSO-d6) δ 9.89 (s, 1H), 7.55-7.43 (m, 2H), 7.37 (d, J=2.5 Hz, 1H), 7.25(d, J=8.6 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.85 (dd, J=8.7, 2.5 Hz, 1H),5.30 (s, 2H), 4.30 (td, J=5.2, 3.7 Hz, 4H). HRMS (ESI⁺): calcd forC₁₅H₁₄ ⁷⁹BrN₂O₃(M+H)⁺, 349.0188; found 349.0187.

Example 138,N-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide

Oxalyl chloride (0.116 mL, 1.375 mmol) was added dropwise to asuspension of 6-quinoline carboxylic acid (198 mg, 1.146 mmol) and DMF(2.217 μL, 0.029 mmol) in dry DCM (7 mL). Anhydrous dioxane (3 mL) wasadded to the reaction in an attempt to fully solubilise all reagents,however this was not entirely successful. The reaction mixture wasstirred at room temperature for 2 h. Pyridine (0.278 mL, 3.44 mmol) wasadded to the reaction followed by Compound 161 (400 mg, 1.146 mmol) inanhydrous dioxane (7 ml). DMF (3 ml) was added in order to dissolve thesolids formed. The reaction was left to stir for 48 h, then concentratedin vacuo to remove solvents. The resulting residue was diluted withwater and extracted with EtOAc (3×20 ml). A solid precipitate wasobserved to form in the aqueous layer. The aqueous layer was ensuredbasic by addition of sat. NaHCO₃ aq. and the beige precipitatecollected. The combined organic layer was washed with brine (25 ml),then dried (Na₂SO₄) to afford the crude product as a brown oil. LCMSshowed that both the precipitate and oil contained product, thereforethe two were combined and purified by biotage chromatography using agradient of 0 to 10% MeOH/DCM to afford the title compound as a whitesolid (236 mg, 41%). ¹H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 10.27(s, 1H), 9.03 (dd, J=4.2, 1.7 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.56 (dd,J=8.2, 1.3 Hz, 2H), 8.30 (dd, J=8.8, 2.0 Hz, 1H), 8.16 (d, J=8.8 Hz,1H), 8.11 (d, J=1.5 Hz, 1H), 7.70-7.69 (m, 2H), 7.66 (dd, J=8.3, 4.2 Hz,1H), 7.58-7.48 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 4.39-4.21 (m, 6H). HRMS(ESI⁺): calcd for C₂₅H₁₉ ⁷⁹BrN₃O₄(M+H)⁺, 504.0559; found 504.0554.

Example 139,N-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide

Oxalyl chloride (0.029 mL, 0.344 mmol) was added drop-wise to a solutionof Compound 70 (118 mg, 0.315 mmol) and DMF (0.554 μL, 7.16 μmol) in dryDCM (3 mL) under argon. The reaction mixture was stirred at roomtemperature for 2.5 h. Compound 161 (100 mg, 0.286 mmol) was then added,followed by pyridine (0.046 mL, 0.573 mmol). The reaction mixture wasnot very homogeneous therefore anhydrous dioxane (2 mL), followed byanhydrous DMF (2 mL) were added. The reaction was allowed to stir atroom temperature for 18 h. The reaction mixture was poured into waterand the aqueous layer washed with EtOAc (1×20 ml). The aqueous layer wasmade basic with sat. NaHCO₃ aq. (to ˜pH 8/9) and then extracted withEtOAc (3×15 ml), the combined organic layer was washed with brine (15ml), dried (Na₂SO₄) and concentrated in vacuo. Purification by biotagechromatography using a gradient of 1 to 10% MeOH/DCM afforded the titlecompound as a beige solid (44 mg, 25%). ¹H NMR (500 MHz, DMSO-d6) δ10.26 (s, 1H), 10.22 (s, 1H) 8.59 (d, J=2.0 Hz, 1H), 8.40 (d, J=8.9 Hz,1H), 8.23 (dd, J=8.7, 2.0 Hz, 1H), 8.10 (s, 1H), 7.88 (d, J=8.7 Hz, 1H),7.69-7.67 (m, 2H), 7.59-7.47 (m, 4H), 7.13 (d, J=8.8 Hz, 3H), 7.00 (d,J=8.4 Hz, 3H), 4.62-4.56 (br m, 2H), 4.35-4.25 (m, 4H), 3.05-2.85 (br m,2H), 2.80-2.50 (br m, 4H), 1.80-1.65 (br m, 4H). HRMS (ESI⁺): calcd forC₃₁H₃₀ ⁷⁹BrN₄O₅(M+H)⁺, 617.1394; found 617.1399.

Example 140,N-(2-cyano-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide

To a solution of Example 138 (150 mg, 0.297 mmol) in anhydrous NMP (2mL) was added copper(I) cyanide (53.1 mg, 0.593 mmol) and the reactionmixture heated to 140° C. in a microwave for 2 h.

The crude reaction mixture was filtered, eluting with EtOAc. The EtOAcwas removed in vacuo and the resulting residue poured into water. Agreen precipitate formed. This precipitate was collected by filtrationand washed with water. Half of the precipitate was taken and purified bypreparative HPLC to afford the product as a beige solid (4 mg, 3%). ¹HNMR (500 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.53 (s, 1H), 9.13 (br s, 1H),8.72 (s, 1H), 8.58 (d, J=8.2 Hz, 1H), 8.30 (d, J=6.4 Hz, 2H), 8.20 (s,2H), 7.84 (q, J=8.6 Hz, 2H), 7.69 (d, J=8.0 Hz, 1H), 7.59-7.48 (m, 2H),7.02 (d, J=8.4 Hz, 1H), 4.42-4.22 (m, 4H). HRMS (ESI⁺): calcd forC₂₆H₁₉N₄O₄ (M+H)⁺, 451.1401; found 451.1397.

Preparation of Compound 162, 5,6,7,8-tetrahydroquinoline-3-carboxylicacid

To a stirring solution of 3-quinoline carboxylic acid (500 mg, 2.89mmol) in trifluoroacetic acid (5.80 mL) was added Adam's catalyst (58mg, 0.255 mmol). The reaction mixture was purged with hydrogen (3×vacuum/hydrogen cycles) and left to stir for 24 h. Further Adam'scatalyst (58 mg, 0.255 mmol) was added and the reaction was allowed tostir for 22.5 h. The reaction mixture was filtered through celite andthe celite pad washed with DCM. The organic solvents were removed invacuo to afford a dark yellow oil. The oil was triturated with diethylether to afford a precipitate that was collected by filtration and driedunder vacuum to afford the title compound as an off-white solid (323 mg,63%). ¹H NMR (500 MHz, DMSO-d6) δ 8.86 (d, J=1.9 Hz, 2H), 8.13 (s, 1H),2.93 (t, J=6.4 Hz, 2H), 2.84 (t, J=6.2 Hz, 2H), 1.88-1.82 (m, 2H),1.81-1.70 (m, 3H). HRMS (ESI⁺): calcd for C₁₀H₁₂NO₂ (M+H)⁺, 178.0868;found 178.0874.

Example 141,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide

To a stirring solution of Compound 162 (37.4 mg, 0.211 mmol) in DMF (1.5mL) at room temperature under argon was added DIEA (0.098 mL, 0.563mmol), followed by HATU (87 mg, 0.229 mmol). The reaction mixture wasallowed to stir for 5 min before Compound 2 (50 mg, 0.176 mmol) wasadded. The reaction mixture was allowed to stir for 16.5 h. The reactionwas diluted with water and the resulting precipitate collected byfiltration, washed with water and dried under vacuum to afford the crudeproduct as a beige solid. Purification by column chromatography using20% EtOAc/DCM, 5% MeOH/DCM, then 10% MeOH/DCM+2% 2M NH₃ in MeOH toafford the title compound as a yellow glass (64 mg, 82%). ¹H NMR (500MHz, DMSO-d6) δ 10.05 (s, 1H), 9.99 (s, 1H), 8.86 (d, J=1.9 Hz, 1H),8.01 (d, J=1.9 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.57 (dd, J=8.3, 2.2 Hz,1H), 7.55-7.46 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H),4.36-4.20 (m, 4H), 2.90-2.87 (m, 2H), 2.83 (t, J=6.2 Hz, 2H), 2.19 (s,3H), 1.85-1.82 (m, 2H), 1.82-1.74 (m, 2H). HRMS (ESI⁺): calcd forC₂₆H₂₆N₃O₄ (M+H)⁺, 444.1918; found 444.1907.

Preparation of Compound 163, 1-(6-bromoquinolin-2-yl)ethanol

To a stirring suspension of Compound 155 (200 mg, 0.847 mmol) in dry THF(2.5 mL) at 0° C. was drop-wise added methylmagnesium bromide (3.0 M indiethyl ether, 0.367 mL, 1.101 mmol). The reaction was allowed to warmgradually to room temperature over 1.5 h. The reaction was partitionedbetween sat. NH₄Cl aq. (30 ml) and EtOAc (30 ml). The aqueous layer wasextracted with a further portion of EtOAc (30 ml). The combined organiclayers were washed with brine (30 ml), dried Na₂SO₄ and concentrated invacuo. Purification by biotage chromatography using a gradient of 6 to80% EtOAc/cyclohexane gave the title compound as a brown oil (148 mg,69%). ¹H NMR (500 MHz, Chloroform-d) δ 8.09 (d, J=8.5 Hz, 1H), 8.01 (d,J=2.2 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 7.81 (dd, J=8.9, 2.2 Hz, 1H),7.40 (d, J=8.5 Hz, 1H), 5.12-4.97 (m, 1H), 4.92-4.75 (br s, 1H), 1.59(d, J=6.6 Hz, 3H). HRMS (ESI⁺): calcd for C₁₁H₁₁ ⁷⁹BrNO (M+H)⁺,252.0015; found 252.0019.

Preparation of Compound 164,6-bromo-2-(1-((tert-butyldimethylsilyl)oxy)ethyl)quinoline

To a solution of Compound 163 (64 mg, 0.254 mmol) in anhydrous DCM (3.0mL) was added imidazole (25.9 mg, 0.381 mmol) followed bytert-butyldimethylsilyl chloride (44.0 mg, 0.292 mmol). The reactionmixture was allowed to stir at room temperature for 19.5 h. The reactionhad not reached completion. Further portions of imidazole (25.9 mg,0.381 mmol) and tert-butyldimethylsilyl chloride (44.0 mg, 0.292 mmol)were added (×3) over a 48 h period and finally the reaction was warmedto 35° C. in an attempt to drive the reaction to completion. Thereaction mixture was diluted with DCM (10 mL) washed with water (1×10mL), 0.25 M HCl (1×10 mL), brine (1×10 mL), dried (MgSO₄), andconcentrated in vacuo. Purification by column chromatography (5%EtOAc/petroleum ether) gave the title compound as a pale yellow oil (64mg, 69%). ¹H NMR (500 MHz, Chloroform-d) δ 8.10 (d, J=8.6 Hz, 1H), 7.99(d, J=2.2 Hz, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.80-7.74 (m, 3H), 5.12 (q,J=6.5 Hz, 1H), 1.54 (d, J=6.5 Hz, 3H), 0.94 (s, 9H), 0.12 (s, 3H), 0.02(s, 3H). HRMS (ESI⁺): calcd for C₁₇H₂₅ ⁷⁹BrNOSi (M+H)⁺, 366.0889; found366.0885.

Preparation of Compound 165,2-(1-((tert-butyldimethylsilyl)oxy)ethyl)quinoline-6-carboxylic acid

To a stirring solution of Compound 164 (62 mg, 0.169 mmol) in dry THF(1.5 mL) at −78° C. was drop-wise added freshly titrated n-BuLi (0.168mL, 0.372 mmol). The reaction was allowed to stir at −78° C. for 40 minbefore solid CO₂ was added. The reaction was stirred at −78° C. for afurther 30 min before it was allowed to warm to room temperature over 17h. The reaction mixture was diluted with water (10 ml). The aqueouslayer was washed with one portion of DCM (15 ml) (an emulsion wasproduced which gradually separated). The aqueous layer was thenacidified using 1 M HCl aq. (to ˜pH 2/3) and extracted with DCM (3×15ml). The combined organic layer was dried (MgSO₄) and concentrated invacuo to afford the crude product as a yellow oil (29 mg, 57%). Thismaterial was used in the next reaction without further purification.

Preparation of Compound 166,2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide

To a stirring solution of Compound 165 (28 mg, 0.084 mmol) in DMF (1.0mL) at room temperature under argon was added DIEA (0.032 mL, 0.186mmol), followed by HATU (41.8 mg, 0.110 mmol). The reaction was allowedto stir for 5 min before Compound 2 (28.8 mg, 0.101 mmol) was added andthe reaction allowed to stir for 16.5 h. The reaction mixture wasdiluted with water (15 ml) and extracted with EtOAc (3×15 ml)—brine wasadded to clear. The combined organic layer was washed with brine (15ml), dried (Na₂SO₄) and concentrated in vacuo. Remaining traces of DMFwere removed by co-evaporation with heptane to afford the crude productas a brown oil. Purification by biotage chromatography using a gradientof 10 to 100% EtOAc/cyclohexane afforded the title compound as a whitesolid (14 mg, 28%). ¹H NMR (500 MHz, Chloroform-d) δ 8.42 (s, 1H), 8.32(d, J=8.6 Hz, 1H), 8.18-8.15 (m, 3H), 7.90 (br s, 1H), 7.87 (br s, 1H),7.85 (d, J=8.6 Hz, 1H), 7.72 (dd, J=8.3, 2.2 Hz, 1H), 7.46 (d, J=2.2 Hz,1H), 7.40 (dd, J=8.4, 2.2 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.96 (d,J=8.4 Hz, 1H), 5.18 (q, J=6.5 Hz, 1H), 4.40-4.23 (m, 4H), 2.38 (s, 3H),1.60 (s, 3H), 1.58 (d, J=6.5 Hz, 3H), 0.96 (s, 9H), 0.15 (s, 3H), 0.05(s, 3H). HRMS (ESI⁺): calcd for C₃₄H₃₆N₃O₅Si (M+H)⁺, 598.2732; found598.2724.

Example 142,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(1-hydroxyethyl)quinoline-6-carboxamide

To a stirring solution of Compound 166 (14 mg, 0.023 mmol) in THF (0.5mL) at room temperature under argon was slowly added TBAF (1M in THF,0.035 mL, 0.035 mmol). The reaction mixture was allowed to stir for 3 h.The reaction was diluted with water (20 ml) and the aqueous layerextracted with EtOAc (3×20 ml). The combined organic layer was washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. Purification bycolumn chromatography using a gradient of 100% DCM then 2.5% to 5% MeOHin DCM afforded the title compound as a yellow solid (9.3 mg, 82%). ¹HNMR (500 MHz, Chloroform-d) δ 8.43 (s, 1H), 8.29 (d, J=8.5 Hz, 1H),8.21-8.16 (m, 3H), 8.14 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.91 (s, 1H),7.66 (dd, J=8.3, 2.2 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.45 (d, J=2.2 Hz,1H), 7.39 (dd, J=8.4, 2.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.95 (d,J=8.4 Hz, 1H), 5.10 (d, J=6.4 Hz, 1H), 4.89 (s, 1H), 4.37-4.27 (m, 4H),2.37 (s, 3H), 1.64 (d, J=6.7 Hz, 3H). HRMS (ESI⁺): calcd for C₂₈H₂₆N₃O₅(M+H)⁺, 484.1867; found 484.1853.

Preparation of Compound 167, methyl1,2,3,4-tetrahydroquinoline-6-carboxylate

A two-necked 250 mL round bottomed flask was charged with methyl6-quinolinecarboxylate (0.500 g, 2.67 mmol) and Pt₂O (0.030 g, 0.13mmol), evacuated and backfilled with argon. TFA (9 mL) was added and theflask was evacuated and backfilled with hydrogen, then sealed and heatedto 60° C. for 5 h, cooled to room temperature, carefully quenched withsat. NaHCO₃ aq. while cooling the flask in a water bath. The mixture wasextracted with DCM (3×) and the organic phases were dried (MgSO₄),filtered and concentrated. The crude material was purified by silica gelcolumn chromatography using a gradient of 14 to 20% EtOAc in petroleumether to afford the title compound as a white solid (232 mg, 45%). ¹HNMR (500 MHz, CDCl₃) δ 7.66-7.62 (m, 2H), 6.39 (d, J=8.9 Hz, 1H), 4.29(br s, 1H), 3.83 (s, 3H), 3.38-3.33 (m, 2H), 2.77 (t, J=6.3 Hz, 2H),1.97-1.89 (m, 2H). HRMS (ESI⁺): calcd for C H₁₄NO₂ (M+H)⁺, 192.1019;found 192.1027.

Preparation of Compound 168, methyl1-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

To a stirring suspension of NaH (31.8 mg, 0.795 mmol) in anhydrous DMF(4 mL) at 0° C. under argon was portion-wise added Compound 167 (76 mg,0.397 mmol). The reaction was allowed to stir at 0° C. for 0.5 h andthen allowed to warm to room temperature for 0.5 h. The flask was cooledto 0° C. and iodomethane (0.037 mL, 0.596 mmol) added. The reaction wasallowed to warm to room temperature and left to stir 19.5 h. Thereaction mixture was poured into water (50 ml) and extracted with EtOAc(2×25 ml)—brine was added to clear. The combined organic layer waswashed with brine (20 ml), dried (Na₂SO₄) and concentrated in vacuo.Purification by biotage chromatography using a gradient of 1 to 10%EtOAc/cyclohexane afforded the title compound as a pale pink solid (54mg, 66%). ¹H NMR (500 MHz, Methanol-d4) δ 7.68 (dd, J=8.8, 2.2 Hz, 1H),7.56-7.50 (m, 2H), 6.56 (d, J=8.7 Hz, 1H), 3.81 (s, 3H), 3.37-3.33 (m,2H), 2.97 (s, 3H), 2.75 (t, J=6.3 Hz, 2H), 2.01-1.91 (m, 2H). HRMS(ESI⁺): calcd for C₁₂H₁₆NO₂ (M+H)⁺, 206.1176; found 206.1186.

Preparation of Compound 169,1-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid

To a stirring solution of Compound 168 (41 mg, 0.200 mmol) in THF (1.8mL) and MeOH (0.6 mL) was added 2M NaOH aq. (0.200 mL, 0.400 mmol). Thereaction was left to stir for 20 h. Further 2M NaOH aq. (0.400 mL, 0.800mmol) was added and the reaction allowed to stir for 6 h, then heated to50° C. and left to stir for 21 h. The solvents were removed in vacuo.The resulting residue was taken up in water (25 ml) and acidified using1 M HCl aq. (to ˜pH 4). The aqueous layer was extracted with EtOAc (2×20ml). The organic layer was washed with 1 M NaOH aq. (2×20 ml) and oncewith water (10 ml). The combined aqueous layer was acidified (to ˜pH2/3) and extracted with EtOAc (2×20 ml) and the combined organic layerwas washed with brine (20 ml) and dried (Na₂SO₄) to afford the titlecompound as an off-white solid (37 mg, 97%). This material was usedwithout further purification. ¹H NMR (500 MHz, Methanol-d4/CDCl₃, 1.5:1)δ 7.70 (dd, J=8.6, 2.1 Hz, 1H), 7.58-7.53 (m, 1H), 6.53 (d, J=8.7 Hz,1H), 3.39-3.33 (m, 2H), 2.97 (s, 2H), 2.76 (t, J=6.3 Hz, 2H), 2.03-1.89(m, 2H). HRMS (ESI⁺): calcd for C₁₁H₁₄NO₂ (M+H)⁺, 192.1025; found192.1019.

Example 143,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a stirring solution of Compound 169 (34 mg, 0.178 mmol) in DMF (1.4mL) at room temperature under argon was added DIEA (0.108 mL, 0.622mmol), followed by HATU (73.2 mg, 0.193 mmol). The reaction was allowedto stir for 5 min before Compound 2 (42.1 mg, 0.148 mmol) was added. Thereaction was allowed to stir for 18 h. Further HATU (73.2 mg, 0.193mmol) and DIEA (0.108 mL, 0.622 mmol) were added and left to stir for afurther 28.5 h. The reaction was poured into water (50 ml) and extractedwith EtOAc (3×20 ml)—brine was added to clear. The organic layer waswashed with a further portion of brine (20 ml), dried (Na₂SO₄) andconcentrated in vacuo to afford a dark pink semi-solid. Purification bybiotage chromatography using a gradient of 5% to 40% EtOAc in DCMafforded the title compound as an off-white solid (6 mg, 9%). ¹H NMR(500 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.42 (s, 1H), 7.77 (d, J=2.1 Hz,1H), 7.69 (dd, J=8.6, 2.2 Hz, 1H), 7.59-7.47 (m, 4H), 7.18 (d, J=8.3 Hz,1H), 6.97 (d, J=8.4 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 4.36-4.23 (m, 4H),3.32-3.25 (m, 2H), 2.92 (s, 3H), 2.74 (t, J=6.3 Hz, 2H), 2.16 (s, 3H),1.95-1.85 (m, 2H). HRMS (ESI⁺): calcd for C₂₇H₂₇N₃O₄ (M+H)⁺, 458.2080;found 458.2069.

Preparation of Compound 170, 2-(6-bromoquinolin-2-yl)ethyl4-methylbenzenesulfonate

To a stirring solution of Compound 6 (400 mg, 1.587 mmol) and DABCO (356mg, 3.17 mmol) in DCM (2.0 mL) at 0° C. under argon was addedtoluenesulfonyl chloride (454 mg, 2.380 mmol). The reaction was allowedto warm to RT and left to stir for 18.5 h, then concentrated in vacuo.The resulting residue was partitioned between EtOAc (25 ml) and 5%NaHCO₃ aq. (30 ml). The aqueous layer was extracted with a furtherportion of EtOAc (25 ml). The combined organic layer was washed withwater (25 ml), dried Na₂SO₄ and concentrated in vacuo to afford thecrude product as a yellow solid. This solid was suspended in a smallamount of EtOAc (3 ml) then heptane was added (15 ml) and the solidtriturated for 2 h. The reaction mixture was left to stand in the fridgeovernight.

The precipitated material was isolated by filtration, washed withheptane and dried under vacuum to afford the product as an off-whitesolid (363 mg, 56%). ¹H NMR (500 MHz, Chloroform-d) δ 7.98-7.94 (m, 2H),7.75-7.73 (m, 2H), 7.61 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.4 Hz, 1H), 7.14(d, J=8.0 Hz, 2H), 4.58 (t, J=6.4 Hz, 2H), 3.29 (t, J=6.4 Hz, 2H), 2.36(s, 3H).

Preparation of Compound 171, 4-(2-(6-bromoquinolin-2-yl)ethyl)morpholine

To a stirring solution of Compound 170 (100 mg, 0.246 mg) in anhydrousacetonitrile (2.5 mL) was added K₂CO₃ (112 mg, 0.812 mmol) followed bymorpholine (0.033 mL, 0.369 mmol). The reaction was heated to 60° C. andallowed to stir for 14 h. The reaction was concentrated in vacuo, thenpartitioned between EtOAc (25 ml) and 5% NaHCO₃ aq (25 ml). The organiclayer was washed with brine (25 ml). However, there was concern thatsome of the product has gone into the aqueous layer. Therefore it wasensured that the aqueous layer was basic by addition of further NaHCO₃aq. This layer was re-extracted with EtOAc (25 ml) and solid NaCl wasadded to the aqueous layer followed by re-extraction with EtOAc (25 ml).The combined organic layer was dried (Na₂SO₄) and concentrated in vacuo.Purification by column chromatography using a gradient of 1 to 5% 2M NH₃in MeOH/EtOAc afforded the title compound as an off-white solid (40 mg,51%). ¹H NMR (500 MHz, Chloroform-d) δ 8.00 (d, J=8.4 Hz, 1H), 7.96 (d,J=2.2 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.76 (dd, J=9.0, 2.2 Hz, 1H),7.37 (d, J=8.5 Hz, 1H), 3.81-3.65 (m, 4H), 3.24-3.09 (m, 2H), 2.95-2.78(m, 2H), 2.64-2.48 (m, 4H).

Example 144,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-morpholinoethyl)quinoline-6-carboxamide

n-Butyllithium (2.01 M in hexanes, 0.139 mL, 0.280 mmol) was addeddrop-wise to a solution of Compound 171 (75 mg, 0.233 mmol) in dry THF(2.0 mL) at −78° C. under argon.

The reaction was allowed to stir at −78° C. for 0.5 h, then solid lumpsof CO₂ were added. The reaction was allowed to warm gradually to roomtemperature with stirring overnight, after which time the reactionmixture was quenched with MeOH and the solvents removed in vacuo toafford the intermediate 2-(2-morpholinoethyl)quinoline-6-carboxylicacid. HATU (116 mg, 0.304 mmol) was added to a solution of the crude2-(2-morpholinoethyl)quinoline-6-carboxylic acid (67 mg, 0.234 mmol) andDIEA (0.090 mL, 0.515 mmol) in dry DMF (2.0 mL). The reaction wasstirred for 5 min, then Compound 2 (73.2 mg, 0.257 mmol) was added andthe reaction allowed to stir at room temperature for 17 h. The reactionmixture was poured into water (30 ml) and extracted with EtOAc (2×30ml)—brine was added to clear. The combined organic layer was washed withbrine (30 ml), dried (Na₂SO₄) and concentrated in vacuo. The initialpurification was carried out using an SCX column, eluting with MeOH then10% 2M NH₃ in MeOH/MeOH. The material was further purified by biotagechromatography using a gradient of 0 to 2% MeOH in DCM to afford thetitle compound as a yellow semi-solid (12 mg, 9.5%). ¹H NMR (500 MHz,DMSO-d6) δ 10.13 (s, 1H), 10.07 (s, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.42(d, J=8.4 Hz, 1H), 8.24 (dd, J=8.8, 2.0 Hz, 1H), 8.05 (d, J=8.7 Hz, 1H),7.90-7.83 (m, 1H), 7.62-7.50 (m, 4H), 7.24 (d, J=8.3 Hz, 1H), 6.98 (d,J=8.4 Hz, 1H), 4.35-4.26 (m, 4H), 3.62-3.51 (m, 1H), 3.16-3.10 (m, 2H),2.86-2.76 (m, 2H), 2.49-2.44 (m, 4H), 2.24 (s, 3H). HRMS (ESI⁺): calcdfor C₃₂H₃₃N₄O₅ (M+H)⁺, 553.2451; found 553.2444.

Preparation of Compound 172, methyl2-(hydroxymethyl)quinoline-6-carboxylate

To a stirring suspension of Compound 13 (256 mg, 1.190 mmol) in ethanol(8 mL) and water (4 mL) at 0° C. was added sodium borohydride (225 mg,5.95 mmol) and the reaction left to stir at 0° C. for 40 min. Thereaction was diluted with water (30 ml) and extracted with EtOAc (3×20ml). The combined organic layer as washed with brine (20 ml), dried(MgSO₄) and concentrated in vacuo to afford the title compound as ayellow solid (248 mg, 96%). ¹H NMR (500 MHz, Chloroform-d) δ 8.62 (d,J=1.9 Hz, 1H), 8.34 (dd, J=8.8, 1.9 Hz, 1H), 8.26 (d, J=8.4 Hz, 1H),8.13 (d, J=8.8 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 4.97 (s, 2H), 4.35 (brs, 1H, OH), 4.02 (s, 3H). HRMS (ESI⁺): calcd for C₁₂H₁₃NO₄ (M+H)⁺,218.0817; found 218.0823.

Preparation of Compound 173, methyl2-(((methylsulfonyl)oxy)methyl)quinoline-6-carboxylate

To a stirring solution of Compound 172 (145 mg, 0.668 mmol) and DMAP(8.15 mg, 0.067 mmol) in DCM (10 mL) at 0° C. under argon was addedtriethylamine (0.279 mL, 2.003 mmol), followed by methanesulfonicanhydride (174 mg, 1.001 mmol). The reaction was allowed to stir at 0°C. for 2 h, the reaction was diluted with DCM (20 ml) and washed withsat. NH₄Cl (aq.) (2×10 ml), sat. NaHCO₃ aq. (1×10 ml), water (1×10 ml)and dried (Na₂SO₄) to afford the title compound as a cream solid (169mg, 86%). ¹H NMR (500 MHz, Chloroform-d) δ 8.64 (d, J=1.8 Hz, 1H),8.39-8.32 (m, 2H), 8.12 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 5.54(s, 2H), 4.02 (s, 3H), 3.17 (s, 3H). HRMS (ESI⁺): calcd for C₁₃H₁₄NO₅S(M+H)⁺, 296.0586; found 296.0589.

Preparation of Compound 174, methyl2-(isopropoxymethyl)quinoline-6-carboxylate

Compound 173 (40 mg, 0.135 mmol) was dissolved in isopropanol (3 mL) andheated to 80° C. in a sealed tube for 15 h. The reaction was dilutedwith water (20 ml) and extracted with EtOAc (3×20 ml). The combinedorganic layer was washed with brine (20 ml), dried (Na₂SO₄) andconcentrated in vacuo to afford the crude product as a yellow/brown oil.Purification by biotage chromatography using a gradient of 5 to 40%EtOAc in DCM afforded the title compound as a yellow solid (25 mg, 80%pure, 60% yield). ¹H NMR (500 MHz, Chloroform-d) δ 8.60 (d, J=1.9 Hz,1H), 8.32-8.26 (m, 2H), 8.08 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H),4.84 (s, 2H), 4.01 (s, 3H), 3.87-3.73 (m, 1H), 1.30 (d, J=6.1 Hz, 6H).HRMS (ESI⁺): calcd for C₁₅H₁₈NO₃ (M+H)⁺, 260.1287; found 260.1285.

Preparation of Compound 175, 2-(isopropoxymethyl)quinoline-6-carboxylicacid

To a stirring solution of Compound 174 (25 mg, 0.096 mmol) in THF (0.6mL) and MeOH (0.2 mL) was added 2M NaOH aq. (0.096 mL, 0.193 mmol). Thereaction was allowed to stir for 18 h at room temperature. Further 2MNaOH aq. (0.096 mL, 0.193 mmol) was added and the reaction heated to 50°C. for 48 h. Finally, LiOH (11.55 mg, 0.482 mmol) was added to thereaction mixture and the reaction allowed to stir at room temperaturefor 2.5 h. The reaction mixture was poured into water (20 ml). Theaqueous layer was acidified using 1M HCl aq. (to ˜pH 3) and extractedwith EtOAc (3×15 ml). The combined organic layer was dried (Na₂SO₄) andconcentrated in vacuo to afford the crude title compound as a darkyellow solid. This material was used directly in the next reactionwithout further purification.

Example 145,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(isopropoxymethyl)quinoline-6-carboxamide

To a stirring solution of Compound 175 (24 mg, 0.098 mmol) in DMF (1.2mL) at room temperature under argon was added DIEA (0.037 mL, 0.215mmol), followed by HATU (48.4 mg, 0.127 mmol). The reaction was allowedto stir for 5 min before Compound 2 (33.4 mg, 0.117 mmol) was added. Thereaction was allowed to stir for 21 h, then diluted with water (20 ml)and extracted with EtOAc (3×10 ml)—brine was added to clear. Thecombined organic layer was washed with brine (10 mL), dried (Na₂SO₄) andconcentrated in vacuo to afford the crude product as a yellow gum.Purification by biotage chromatography using a gradient of 30% to 50%EtOAc in DCM (it was necessary to carry out two biotage purifications toafford sufficiently pure material) afforded the title compound as apeach solid (10 mg, 20%). ¹H NMR (500 MHz, Methanol-d4) δ 8.62 (d, J=1.6Hz, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.32 (dd, J=8.8, 1.9 Hz, 1H), 8.14 (d,J=8.8 Hz, 1H), 7.85-7.78 (m, 2H), 7.56 (dd, J=8.3, 2.2 Hz, 1H),7.52-7.45 (m, 2H), 7.32 (d, J=8.4 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 4.84(s, 2H), 4.38-4.24 (m, 4H), 3.86 (hept, J=6.4 Hz, 1H), 2.35 (s, 3H),1.31 (d, J=6.1 Hz, 6H). HRMS (ESI⁺): calcd for C₃₀H₂₉N₃O₅ (M+H)⁺,512.2180; found 512.2174.

Preparation of Compound 176, methyl2-(((tetrahydrofuran-2-yl)methoxy)methyl)quinoline-6-carboxylate

Compound 173 (50 mg) was dissolved in tetrahydrofurfuryl alcohol (3 mL)and heated to 80° C. for 3 days. The reaction was diluted with water (20ml) and extracted with EtOAc (3×20 ml). The combined organic layer waswashed with brine (20 ml) and dried (Na₂SO₄) to afford the crude productas a yellow/brown oil. Initial purification was carried out by SCXchromatography, eluting with MeOH and then MeOH+2M NH₃ in MeOH. Theresulting residue was further purified by biotage chromatography using agradient of 8% to 100% EtOAc in DCM to afford the title compound as ayellow/brown solid (14 mg, 27%). ¹H NMR (500 MHz, Chloroform-d) δ 8.60(d, J=1.8 Hz, 1H), 8.34-8.26 (m, 2H), 8.09 (d, J=8.8 Hz, 1H), 7.76 (d,J=8.5 Hz, 1H), 4.93 (d, J=14.0 Hz, 1H), 4.89 (d, J=14.0 Hz, 1H), 4.19(qd, J=7.0, 4.0 Hz, 1H), 4.01 (s, 3H), 3.97-3.91 (m, 1H), 3.88-3.78 (m,1H), 3.71-3.57 (m, 2H), 2.07-1.85 (m, 3H), 1.75-1.63 (m, 1H). HRMS(ESI⁺): calcd for C₁₇H₂₀NO₄ (M+H)⁺, 302.1392; found 302.1387.

Example 146,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(((tetrahydrofuran-2-yl)methoxy)methyl)quinoline-6-carboxamide

To a stirring solution of Compound 176 (14 mg, 0.046 mmol) in THF (0.3mL) and methanol (0.1 mL) was added a solution of LiOH (11.13 mg, 0.465mmol) in water (0.1 mL) The reaction was allowed to stir at roomtemperature for 4 h. The reaction was diluted with water (20 ml) and theaqueous layer made acidic by addition of 1 M HCl aq. (to ˜pH 3). Theaqueous layer was extracted with EtOAc (3×10 ml). The combined organiclayer was dried (Na₂SO₄) and concentrated in vacuo to afford2-(((tetrahydrofuran-2-yl)methoxy)methyl)quinoline-6-carboxylic acid asa brown oil. To a stirring solution of2-(((tetrahydrofuran-2-yl)methoxy)methyl)quinoline-6-carboxylic acid (14mg, 0.049 mmol) in DMF (0.75 mL) at room temperature under argon wasadded DIEA (0.019 mL, 0.107 mmol), followed by HATU (24.09 mg, 0.063mmol). The reaction was allowed to stir for 5 min before Compound 2(16.62 mg, 0.058 mmol) was added. The reaction was allowed to stir for21 h, then diluted with water (20 ml) and extracted with EtOAc (3×10ml)—brine was added to clear. The combined organic layer was washed withbrine (10 mL), dried (Na₂SO₄) and concentrated in vacuo to afford thecrude product as a yellow/orange gum. Purification by columnchromatography using a gradient of 25% to 75% EtOAc in DCM afforded thetitle compound as a yellow solid (10.5 mg, 39%). ¹H NMR (500 MHz,Methanol-d4) δ 8.61 (d, J=1.6 Hz, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.31 (dd,J=8.8, 1.8 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.86-7.75 (m, 2H), 7.54 (dd,J=8.3, 2.2 Hz, 1H), 7.52-7.43 (m, 2H), 7.30 (d, J=8.4 Hz, 1H), 6.94 (d,J=8.4 Hz, 1H), 4.89 (s, 2H), 4.36-4.28 (m, 4H), 4.21 (qd, J=7.0, 3.7 Hz,1H), 3.96-3.88 (m, 1H), 3.87-3.78 (m, 1H), 3.73-3.60 (m, 2H), 3.33 (dt,J=3.3, 1.4 Hz, 2H), 2.35 (s, 3H), 2.11-1.88 (m, 3H), 1.78-1.70 (m, 1H).HRMS (ESI⁺): calcd for C₃₂H₃₂N₃O₆ (M+H)⁺, 554.2286; found 554.2279.

Preparation of Compound 177, methyl2-((2-hydroxyethoxy)methyl)quinoline-6-carboxylate

A solution of Compound 173 (200 mg, 0.677 mmol) in ethylene glycol (4.5mL, 82 mmol) was warmed to 80° C. for 24 h. The reaction was allowed tocool to room temperature then diluted with water (40 ml) and extractedwith EtOAc (3×15 ml)—brine was added to clear. The combined organiclayer was washed with water (30 ml), brine (30 ml) and dried (Na₂SO₄),then concentrated in vacuo to afford the crude product as a brown oil(123 mg). Purification by column chromatography using a gradient of 8%to 100% EtOAc in DCM afforded the title compound as a beige solid (72mg, 41%). ¹H NMR (500 MHz, Chloroform-d) δ 8.62 (d, J=1.8 Hz, 1H), 8.33(dd, J=8.8, 1.9 Hz, 1H), 8.30 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.8 Hz, 4H),7.59 (d, J=8.5 Hz, 4H), 4.94 (s, 2H), 4.02 (s, 3H), 3.90-3.86 (m, 2H),3.85-3.82 (m, 2H), 3.54 (br s, 1H, OH). HRMS (ESI⁺): calcd for C₁₄H₁₆NO₄(M+H)⁺, 262.1079; found 262.1074.

Preparation of Compound 178, methyl2-((2-(pyrrolidin-1-yl)ethoxy)methyl)quinoline-6-carboxylate

To a stirring solution of Compound 177 (68 mg, 0.260 mmol) in DCM (2.5mL) at 0° C. under argon was added DMAP (3.18 mg, 0.026 mmol) followedby triethylamine (0.109 mL, 0.781 mmol) and methanesulfonic anhydride(68.0 mg, 0.390 mmol). The reaction was left to stir at 0° C. for 3 h.The reaction was diluted with DCM (20 ml) and washed with sat. NH₄Cl(aq.) (2×10 mL), NaHCO₃ aq. (1×10 mL), water (1×10 mL), brine (1×10 mL)and dried (Na₂SO₄), then concentrated in vacuo to afford methyl2-((2-((methylsulfonyl)oxy)ethoxy)methyl)quinoline-6-carboxylate as abrown oil. To a stirring solution of methyl2-((2-((methylsulfonyl)oxy)ethoxy)methyl)quinoline-6-carboxylate (88 mg,0.259 mmol) in dry DCM (2.5 mL) at 0° C. under argon was addedpyrrolidine (0.216 mL, 2.59 mmol). The reaction was then allowed to warmgradually to room temperature and allowed to stir for 22 h. The reactionwas diluted with sat. NaHCO₃ aq. (20 ml) and extracted with EtOAc (3×15ml). The combined organic layer was washed with brine (20 ml), driedNa₂SO₄ and concentrated in vacuo to afford the crude product as a greenoil. Purification by biotage chromatography with a KP-NH column andusing a gradient of 8% to 100% EtOAc in cyclohexane afforded the titlecompound as a waxy yellow/brown solid (41 mg, 50%). ¹H NMR (500 MHz,Chloroform-d) δ 8.61 (d, J=1.8 Hz, 1H), 8.35-8.25 (m, 2H), 8.10 (d,J=8.8 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 4.89 (s, 2H), 4.02 (s, 3H), 3.76(t, J=5.9 Hz, 2H), 2.81 (t, J=5.9 Hz, 2H), 2.64-2.57 (m, 4H), 1.84-1.78(m, 4H). HRMS (ESI⁺): calcd for C₁₈H₂₃N₂O₃ (M+H)⁺, 315.1709; found315.1702.

Preparation of Compound 179,2-((2-(pyrrolidin-1-yl)ethoxy)methyl)quinoline-6-carboxylic acid

To a stirring solution of Compound 178 (36 mg, 0.115 mmol) in THF (1.5mL) and MeOH (0.5 mL) was added 2M NaOH aq. (0.286 mL, 0.573 mmol) andthe reaction left to stir for 19 h at room temperature. Further 2M NaOHaq. (0.286 mL, 0.573 mmol) was added and the reaction heated to 50° C.for 4 h. The reaction mixture was diluted with water (20 ml) andacidified with 1 M maleic acid aq. (to ˜pH 3). The aqueous layer waswashed twice with EtOAc (2×15 mL) and concentrated in vacuo to affordthe crude product as a pale brown solid. Purification of this materialby SCX chromatography eluting with a gradient of 0 to 10% 2M NH₃ inMeOH/MeOH gave the title compound as a brown oil (27 mg, 79%). HRMS(ESI⁺): calcd for C₁₇H₂₁N₂O₃ (M+H)⁺, 301.1552; found 301.1548.

Example 147,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((2-(pyrrolidin-1-yl)ethoxy)methyl)quinoline-6-carboxamide

To a stirring solution of Compound 179 (27 mg, 0.090 mmol) in DMF (1.0mL) at room temperature under argon was added DIEA (0.050 mL, 0.288mmol), followed by HATU (44.4 mg, 0.117 mmol). The reaction was allowedto stir for 5 min before Compound 2 (30.7 mg, 0.108 mmol) was added. Thereaction was allowed to stir for 15 h, then the reaction was dilutedwith water (20 ml) and extracted with EtOAc (3×15 ml)—brine was added toclear. Some solids were deposited around the side of the separatingflask—these were dissolved in a small amount MeOH and added to theorganic layer. The combined organic layer was washed with brine (20 ml),dried (Na₂SO₄) and concentrated in vacuo. Purification by columnchromatography using initially 50% EtOAc/DCM, followed by using agradient of 2% to 10% MeOH/DCM+1% 2M NH₃ in MeOH afforded a pale greysolid that was unfortunately insufficiently pure by ¹H NMR. An attemptto further purify this material by SCX chromatography failed. Finallythe material was purified by preparative TLC (eluting with 2×10%MeOH/DCM) to afford the title compound as an off-white solid (3.2 mg,6%). ¹H NMR (500 MHz, Methanol-d4) b 8.66-8.61 (m, 1H), 8.56 (d, J=8.5Hz, 1H), 8.34 (dd, J=8.8, 1.8 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.88-7.78(m, 2H), 7.55 (dd, J=8.3, 2.2 Hz, 1H), 7.51-7.47 (m, 2H), 7.33 (d, J=8.4Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 4.42-4.23 (m, 4H), 3.88 (t, J=5.5 Hz,2H), 3.14-3.08 (m, 2H), 3.01-2.92 (m, 4H), 2.36 (s, 3H), 1.98-1.93 (m,4H). HRMS (ESI⁺): calcd for C₃₃H₃₄N₄O₅ (M+H)⁺, 567.2602; found 567.2594.

Preparation of Compound 180, ethyl5-((2-(pyrrolidin-1-yl)ethyl)amino)quinoline-3-carboxylate

Ethyl 5-chloroquinoline-3-carboxylate (50 mg, 0.212 mmol), BrettPhos(22.8 mg, 0.042 mmol), Pd(OAc)₂ (4.7 mg, 0.021 mmol), K₂CO₃ (58.6 mg,0.424 mmol) and 1-(2-aminoethyl)-pyrrolidine (0.022 mL, 0.170 mmol) werecombined in anhydrous t-butanol (2.0 mL), degassed by 3× vacuum/argoncycles and heated to 80° C. for 18 h. The solvent was removed in vacuoand the resulting residue was partitioned between water (25 ml) andEtOAc (25 ml). The aqueous layer was acidified using 1 M HCl aq. (to ˜pH4.0). The aqueous and organic layers were separated and the aqueouslayer washed with a further portion of EtOAc (25 ml). The aqueous layerwas then concentrated in vacuo to afford the crude product as a redsolid. Purification by biotage chromatography with a KP-NH column usinga gradient of 0 to 60% EtOAc/cyclohexane afforded the title compound asa yellow oil (20 mg, 30%). ¹H NMR (500 MHz, Chloroform-d) δ 9.39 (d,J=2.0 Hz, 1H), 8.95 (dd, J=1.9, 0.7 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H),7.48 (d, J=8.4 Hz, 1H), 6.65 (d, J=7.7 Hz, 1H), 5.50 (br s, 1H, NH),4.49 (q, J=7.1 Hz, 2H), 3.43-3.27 (m, 2H), 3.02-2.82 (m, 2H), 2.70-2.50(m, 4H), 1.91-1.78 (m, 4H), 1.48 (t, J=7.1 Hz, 3H). HRMS (ESI⁺): calcdfor C₁₈H₂₃N₃O₂ (M+H)⁺, 314.1869; found 314.1847.

Example 148,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-5-((2-(pyrrolidin-1-yl)ethyl)amino)quinoline-3-carboxamide

To a stirring solution of Compound 180 (20 mg, 0.064 mmol) in THF (1.5mL) and MeOH (0.5 mL) was added 2M NaOH aq. (0.22 mL, 0.447 mmol). Thereaction was allowed to stir at room temperature for 17 h. The reactionmixture was concentrated in vacuo and the resulting residue was dilutedwith water (20 ml) and the aqueous layer acidified with 1M HCl aq. (to˜pH 2/3). The aqueous layer was washed with EtOAc (20 ml) and thenconcentrated in vacuo to afford5-((2-(pyrrolidin-1-yl)ethyl)amino)quinoline-3-carboxylic acid as a redsolid. To a stirring solution of5-((2-(pyrrolidin-1-yl)ethyl)amino)quinoline-3-carboxylic acid (21 mg,0.065 mmol) in DMF (0.5 mL) at room temperature under argon was addedDIEA (0.040 mL, 0.228 mmol), followed by HATU (26.9 mg, 0.071 mmol). Thereaction was allowed to stir for 5 min before Compound 2 (15.46 mg,0.054 mmol) was added. The reaction was left to stir for 16 h, thendiluted with water and the resulting precipitate collected by filtrationand washed well with water, air dried and further dried under vacuum toafford the crude product as a yellow solid. Purification by columnchromatography using a gradient of 5% to 10% MeOH in DCM+2% 2M NH₃ inMeOH afforded the title compound as a bright yellow solid (5 mg, 17%).¹H NMR (500 MHz, Methanol-d4) δ 9.33 (br s, 2H), 7.89 (d, J=2.2 Hz, 1H),7.75 (t, J=8.1 Hz, 1H), 7.55-7.42 (m, 4H), 7.32 (d, J=8.4 Hz, 1H), 6.96(d, J=8.4 Hz, 1H), 6.85 (d, J=7.9 Hz, 1H) 4.47-4.13 (m, 4H), 3.69 (t,J=6.1 Hz, 1H), 3.39-3.35 (m, 2H), 3.24-3.17 (m, 4H), 2.36 (s, 3H),2.06-2.01 (m, 4H). HRMS (ESI⁺): calcd for C₃₂H₃₃N₅O₄ (M+H)⁺, 552.2605;found 552.2591.

Preparation of Compound 181,N-(4-chloro-3-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

Oxalyl chloride (0.141 mL, 1.665 mmol) was added dropwise to a solutionof 1,4-benzodioxane-6-carboxylic acid (250 mg, 1.388 mmol) and DMF (2.69μL, 0.035 mmol) in dry DCM (7 mL). The reaction was allowed to stir atroom temperature for 2 h. The reaction mixture was concentrated, afurther portion of dry DCM (7 ml) was added and concentrated again. Thisresidue was re-dissolved in dry DCM (3+3+1 mL) and added drop-wise to asolution of 4-chloro-3-nitroaniline (239 mg, 1.388 mmol) and pyridine(0.224 mL, 2.78 mmol) in dry DCM (7 mL). The reaction was allowed tostir for 3 h at room temperature. The solvent was removed in vacuo andthe resulting residue was suspended in MeOH and a solid precipitated byaddition of water. The precipitate was isolated by filtration and washedwith water, then dried under high vacuum to afford the title compound asa dark yellow solid (417 mg, 90%). ¹H NMR (500 MHz, DMSO-d6) δ 10.54 (s,1H), 8.59 (d, J=2.5 Hz, 1H), 8.05 (dd, J=8.9, 2.5 Hz, 1H), 7.75 (d,J=8.9 Hz, 1H), 7.59-7.46 (m, 2H), 7.02 (d, J=8.4 Hz, 1H), 4.35-4.28 (m,6H). HRMS (ESI⁺): calcd for C₁₅H₁₂ClN₂O₅ (M+H)⁺, 335.0435; found335.0437.

Preparation of Compound 182, N-(3-amino-4-chlorophenyl)-2,3dihydrobenzo[b][1,4]dioxine-6-carboxamide

To a stirring suspension of Compound 181 (200 mg, 0.598 mmol) in EtOH (3mL) and water (1.0 mL) was added Fe powder (234 mg, 4.18 mmol) and NH₄Cl(224 mg, 4.18 mmol). The reaction mixture was then heated to reflux for15 h. The reaction was filtered through celite (eluting withEtOH/EtOAc). The solvents were removed in vacuo and the resultingresidue partitioned between water (30 ml) and EtOAc (30 ml). The organiclayer was washed with sat. NaHCO₃ aq. (30 ml), water (30 ml), brine (30ml) and dried (Na₂SO₄), then concentrated in vacuo to afford the crudeproduct as a dark orange solid (143 mg, 79%). ¹H NMR (500 MHz, DMSO-d6)δ 9.88 (s, 1H), 7.51-7.44 (m, 2H), 7.36 (d, J=2.4 Hz, 1H), 7.10 (d,J=8.6 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.89 (dd, J=8.7, 2.5 Hz, 1H),5.34 (s, 2H, NH₂), 4.31-4.27 (m, 4H). HRMS (ESI⁺): calcd forC₁₅H₁₄ClN₂O₃ (M+H)⁺, 305.0693; found 305.0705.

Example 149,N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide

Oxalyl chloride (0.025 mL, 0.295 mmol) was added drop-wise to a solutionof 6-quinoline carboxylic acid (46.9 mg, 0.271 mmol) and DMF (0.476 μL,6.15 μmol) in dry DCM (2.5 mL). Dioxane (3 ml) was added in an attemptto further solubilise the material but this was ineffective. Thereaction allowed to stir at room temperature for 3 h. The reaction wasconcentrated in vacuo, a further portion of anhydrous DCM (2.5 mL) wasadded and concentrated again. This residue was re-suspended in anhydrousDCM (2.0 mL). A solution of Compound 182 (75 mg, 0.246 mmol) andpyridine (0.060 mL, 0.738 mmol) in dry DCM (2 mL) and dioxane (1 mL) wasprepared and added slowly to the acid chloride suspension. The reactionwas allowed to stir for 18 h, then the solvents were removed in vacuo.The resulting residue was suspended in MeOH and diluted with water. Theprecipitate formed was isolated by filtration, washed with water anddried under high vacuum to afford the crude product as a yellow solid.Purification by preparative HPLC gave the title compound as a whitesolid (10 mg, 9%). ¹H NMR (500 MHz, DMSO-d6) δ 10.37 (1H, s), 10.28 (1H,s), 9.03 (dd, J=4.2, 1.7 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H), 8.56 (br d,J=7.5 Hz, 1H), 8.29 (dd, J=8.8, 2.0 Hz, 1H), 8.20-8.10 (m, 2H), 7.75(dd, J=8.8, 2.5 Hz, 1H), 7.66 (dd, J=8.3, 4.2 Hz, 1H), 7.58-7.48 (m,2H), 7.00 (d, J=8.4 Hz, 1H), 4.41-4.24 (m, 4H). HRMS (ESI⁺): calcd forC₂₅H₁₉ClN₃O₄ (M+H)⁺, 460.1056; found 460.1056.

Preparation of Compound 183, 6-bromo-2-chloro-3-iodoquinoline

To a stirring suspension of 6-bromo-2-chloroquinoline (1 g, 4.12 mmol)at −78° C. in dry THF (35 ml) was drop-wise added LDA (2.0 M inTHF/Heptane/Ethyl benzene, 2.062 mL, 4.12 mmol). The reaction wasallowed to stir at −78° C. for 2 h before the addition of iodine (1.047g, 4.12 mmol) in THF (5 ml). The reaction was stirred at −78° C. for afurther 2.5 h before 20% water/THF (10 ml) was added to quench thereaction. The reaction was diluted with further water (20 ml) at −10° C.The THF was removed in vacuo and the resulting aqueous layer extractedwith EtOAc (1×10) and ether (2×10). Some solids which formed around thesides of the separating funnel could be dissolved using a small amountof DCM and were added to the organic layer. The combined organic layerwas washed twice with 10% sodium thiosulfate (2×15 ml), water (20 ml),brine (20 ml) and dried (Na₂SO₄). Purification by short columnchromatography (19:1 cyclohexane/EtOAc) gave the title compound as apale yellow solid (627 mg, 41%). ¹H NMR (500 MHz, Chloroform-d) δ 8.60(s, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.83 (dd,J=9.0, 2.1 Hz, 1H). HRMS (ESI⁺): calcd for C₉H₅BrClIN (M+H)⁺, 367.8333;found 367.8330.

Preparation of Compound 184,6-bromo-3-iodo-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline

To a stirring suspension of NaH (37.5 mg, 0.936 mmol) in THF (3.0 mL) at0° C. under argon was slowly added 1-(2-hydroxyethyl)pyrrolidine (0.114mL, 0.977 mmol). The reaction mixture was allowed to stir for 5 min at0° C., then allowed to warm to room temperature for 30 min. Compound 183(300 mg, 0.814 mmol) was then added and the reaction heated to refluxfor 16 h. The reaction was concentrated in vacuo and the resultingresidue diluted with water (20 ml) and sat. NaHCO₃ aq. (10 ml). Theaqueous layer was extracted with DCM (3×15 ml) and the combined organiclayer was washed with water (20 ml) and dried (MgSO₄). Purification bybiotage chromatography using a gradient of 2% to 10% MeOH/DCM affordedthe title compound as an off-white solid (323 mg, 89%). ¹H NMR (500 MHz,Chloroform-d) δ 8.44 (s, 1H), 7.78 (d, J=1.8 Hz, 1H), 7.71-7.68 (m, 2H),4.69 (t, J=6.0 Hz, 2H), 3.04 (t, J=6.0 Hz, 2H), 2.80-2.75 (m, 4H),1.89-1.83 (m, 4H). HRMS (ESI⁺): calcd for C₁₅H₁₆ ⁷⁹BrIN₂O (M+H)⁺,446.9563; found 446.9559.

Preparation of Compound 185,6-bromo-N-(2-methoxyethyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinolin-3-amine

Compound 184 (201 mg, 0.450 mmol), cesium carbonate (293 mg, 0.899mmol), 2-methoxyethylamine (0.586 mL, 6.74 mmol) and2-isobutyrylcyclohexanone (15.13 mg, 0.090 mmol) were combined in amicrowave vial in anhydrous DMF (2.2 mL) and degassed by 3× vacuum/argoncycles. Copper(I) iodide (4.28 mg, 0.022 mmol) was added, the reactiondegassed again via the same procedure and heated to 125° C. for 4 h. Thereaction was poured into water (20 ml) and extracted with EtOAc (3×20ml)—brine was added to clear. The combined organic layer was washed withbrine (20 mL), dried Na₂SO₄ and concentrated in vacuo. Remaining tracesof DMF were removed by co-evaporation with heptane. Purification bycolumn chromatography using a gradient of 2% to 10% MeOH/DCM gave thetitle compound as a 2:1 mixture with the corresponding des-iodo compound(97 mg, 36% title compound). HRMS (ESI⁺): calcd for C₁₈H₂₅ ⁷⁹BrN₃O₂(M+H)⁺, 394.1130; found 394.1125.

Preparation of Compound 186, butyl3-((2-methoxyethyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxylate

To a stirring solution of crude Compound 185 (94 mg, 0.238 mmol) in1-butanol (0.75 ml) was added Hermann's catalyst (11.18 mg, 0.012 mmol)and tri-t-butylphosphonium tetrafluoroborate (13.83 mg, 0.048 mmol),followed by molybdenum hexacarbonyl (126 mg, 0.477 mmol) and DBU (1.0Min THF, 0.715 mL, 0.715 mmol). The reaction was heated to 130° C. in amicrowave for 1 h, then filtered through celite and the solvent removedin vacuo. Purification by column chromatography using a gradient of 2%to 8% MeOH/DCM gave the title compound as a dark yellow oil as a 2:1mixture with the des-iodo compound from the previous step (80 mg, 53%title compound). HRMS (ESI⁺): calcd for C₂₃H₃₃N₃O₄ (M+H)⁺, 416.2549;found 416.2550.

Preparation of Compound 187,3-((2-methoxyethyl)amino)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxylicacid

To a stirring solution of crude Compound 186 (72 mg, 0.173 mmol) in THF(1.5 mL) and MeOH (0.5 mL) was added 2M NaOH aq. (0.433 mL, 0.866 mmol)and the reaction left to stir at room temperature for 18 h. Further 2MNaOH aq. (0.433 mL, 0.866 mmol) was added and the reaction heated to 50°C. for 4 h. The reaction was diluted with water (20 ml) and acidifiedwith 1 M HCl aq. (to ˜pH 3). The aqueous layer was washed with DCM (2×20ml), then concentrated in vacuo to afford the title compound as a brownsemi-solid, still as a 2:1 mixture with the des-iodo analogue carriedthrough from the previous steps. This material was used directly in thenext reaction without further purification. HRMS (ESI⁺): calcd forC₁₉H₂₆N₃O₄ (M+H)⁺, 360.1923; found 360.1922.

Example 150,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-3-((2-methoxyethyl)amino)-2-(2-(Pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide

To a stirring solution of crude Compound 187 (62 mg, 0.173 mmol) in DMF(1.5 mL) at room temperature under argon was added DIEA (0.096 mL, 0.552mmol), followed by HATU (85 mg, 0.224 mmol). The reaction was allowed tostir for 5 min before Compound 2 (58.9 mg, 0.207 mmol) was added. Thereaction was left to stir for 2 days, then diluted with water (20 ml)and the aqueous layer extracted with EtOAc (3×15 ml). The combinedorganic layer was washed with brine (2×10 ml), then concentrated invacuo. Remaining traces of DMF were removed by co-evaporation withheptane (×2). Purification by column chromatography initially using 4:1DCM/EtOAc, then using a gradient of 2.5% to 10% MeOH/DCM gave the titlecompound as a pale yellow solid (16 mg, 15%). ¹H NMR (500 MHz,Chloroform-d) δ 8.12 (d, J=2.1 Hz, 1H), 8.09 (s, 1H), 8.01 (br s, 1H),7.96 (br s, 1H), 7.79-7.72 (m, 3H), 7.46 (d, J=2.1 Hz, 1H), 7.40 (dd,J=8.4, 2.2 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.89(s, 2H), 5.21 (br s, 1H, NH), 4.73 (t, J=5.8 Hz, 2H), 4.34-4.28 (m, 4H),3.75-3.71 (m, 2H), 3.44 (s, 3H), 3.43-3.38 (m, 2H), 3.04 (t, J=5.8 Hz,2H), 2.75-2.70 (m, 4H), 2.35 (s, 3H), 1.89-1.82 (m, 4H). HRMS (ESI⁺):calcd for C₃₅H₃₉N₅O₆ (M+H)⁺, 626.2973; found 626.2969.

Preparation of Compound 188, methyl2-(isobutoxymethyl)quinoline-6-carboxylate

Compound 173 (100 mg, 0.339 mmol) was combined with 2-methoxy-1-propanoland heated to 80° C. for 2 days. The reaction was diluted with water (25ml) and extracted with EtOAc (3×20 ml). The combined organic layer waswashed with brine (25 ml), dried (Na₂SO₄) and concentrated in vacuo.Purification by biotage chromatography using a gradient of 1% to 10%EtOAc/DCM gave the title compound as a yellow solid (39 mg, 42%). ¹H NMR(500 MHz, Chloroform-d) δ 8.61 (d, J=1.8 Hz, 1H), 8.33-8.29 (m, 2H),8.10 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 4.84 (s, 2H), 4.02 (s,3H), 3.40 (d, J=6.6 Hz, 2H), 2.06-1.97 (m, 1H), 1.00 (d, J=6.7 Hz, 6H).HRMS (ESI⁺): calcd for C₁₆H₂₀NO₃ (M+H)⁺, 274.1443; found 274.1443.

Preparation of Compound 189, 2-(isobutoxymethyl)quinoline-6-carboxylicacid

To a stirring solution of Compound 188 (36 mg, 0.132 mmol) in THF (0.9mL) and MeOH (0.3 mL) was added a solution of LiOH (31.5 mg, 1.317 mmol)in water (0.3 mL). The reaction was stirred at room temperature for 2.5h. The reaction mixture was diluted with water (20 ml) and acidifiedusing 1M HCl aq. (to ˜pH3). The aqueous layer was extracted with EtOAc(3×15 ml). The combined organic layer was dried (Na₂SO₄) andconcentrated in vacuo to afford the title compound as a pale yellowsolid. This crude material was used directly in the next reactionwithout further purification. HRMS (ESI⁺): calcd for C₁₅H₁₈N₀₃ (M+H)⁺,260.1287; found 260.1288.

Example 151,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(isobutoxymethyl)quinoline-6-carboxamide

To a stirring solution of Compound 189 (35 mg, 0.135 mmol) in DMF (2.0mL) at room temperature under argon was added DIEA (0.052 mL, 0.297mmol), followed by HATU (66.7 mg, 0.175 mmol). The reaction was allowedto stir for 5 min before Compound 2 (46.1 mg, 0.162 mmol) was added. Thereaction was left to stir at room temperature for 23 h, then dilutedwith water (25 ml) and extracted with EtOAc (3×20 ml)—brine was added toclear. The combined organic layer was washed with brine (20 ml), dried(MgSO₄) and concentrated in vacuo. Co-evaporation with heptane was usedto remove remaining traces of DMF. Purification by column chromatographyusing a gradient of 20% to 50% EtOAc/DCM gave the title compound as anoff-white solid (41 mg, 58%). ¹H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H),10.08 (s, 1H), 8.66 (d, J=1.8 Hz, 1H), 8.56 (d, J=8.5 Hz, 1H), 8.28 (dd,J=8.8, 1.9 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.70(d, J=8.5 Hz, 1H), 7.59 (dd, J=8.3, 2.2 Hz, 1H), 7.55-7.50 (m, 2H), 7.25(d, J=8.5 Hz, 2H), 6.98 (d, J=8.4 Hz, 1H), 4.76 (s, 2H), 4.35-4.27 (m,4H), 2.69 (s, 3H), 2.25 (s, 3H), 1.98-1.87 (m, 1H), 0.93 (d, J=6.7 Hz,6H). HRMS (ESI⁺): calcd for C₃₁H₃₁N₃O₅(M+H)⁺, 526.2336; found 526.2327.

Preparation of Compound 190,2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid

To a stirring solution of 2-methylquinoline-6-carboxylic acid (250 mg,1.336 mmol) in MeOH (10 mL) under argon was added palladium on carbon(10% wt, 35 mg), followed by ammonium formate (842 mg, 13.36 mmol). Thereaction was heated to reflux and left to stir for 2 days (furtherportions of palladium on carbon (×1) and ammonium formate (×2) wereadded in order to drive the reaction to completion). The reactionmixture was filtered through celite and the solvents removed in vacuo.The resulting residue was taken up in water (30 ml) and made acidic bythe addition of 1M HCl aq. (to ˜pH 3). The aqueous layer was extractedwith DCM (3×15 ml), the combined organic layer was dried (Na₂SO₄) andconcentrated in vacuo to afford the title compound as a white solid (170mg, 67%). ¹H NMR (500 MHz, DMSO-d6) δ 11.86 (s, 1H), 7.47-7.43 (m, 2H),6.46-6.42 (m, 2H), 3.43-3.32 (m, 2H), 2.76-2.62 (m, 2H), 1.90-1.83 (m,1H), 1.46-1.36 (m, 1H), 1.16 (d, J=6.3 Hz, 3H).

Preparation of Compound 191,1-(((9H-fluoren-9-yl)methoxy)carbonyl)-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

Fmoc chloride (82 mg, 0.316 mmol) was added to a stirring solution ofCompound 190 (55 mg, 0.288 mmol) and NaOH aq. 0.5 M (1.2 ml, 0.600 mmol)in dioxane (1.2 mL) at room temperature. The reaction was allowed tostir at room temperature for 19 h, then partitioned between DCM (20 ml)and 1M HCl aq. (20 ml). The aqueous layer was extracted with further DCM(20 ml) and the combined organic layer was washed with water (20 ml),brine (20 ml), dried (Na₂SO₄) and concentrated in vacuo to afford thecrude material as a colourless oil (45 mg, 39%). ¹H NMR (500 MHz,DMSO-d6) δ 12.67 (br s, 1H), 7.90 (dd, J=12.1, 7.5 Hz, 2H), 7.66-7.61(m, 3H), 7.50-7.29 (m, 5H), 7.14 (br d, J=8.3 Hz, 1H), 4.80 (dd, J=10.8,5.1 Hz, 1H), 4.62 (dd, J=10.8, 5.1 Hz, 1H), 4.35 (t, J=5.0 Hz, 1H),4.32-4.26 (m, 2H), 2.73-2.66 (m, 1H), 2.58-2.50 (m, 1H), 2.01-1.93 (m,1H), 1.47-1.39 (m, 1H), 0.89 (d, J=6.5 Hz, 3H). HRMS (ESI⁺): calcd forC₂₆H₂₃N₃₀₄ (M+H)⁺, 414.1692; found 414.1687.

Preparation of Compound 192, (9H-fluoren-9-yl)methyl6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

To a stirring solution of Compound 191 (31 mg, 0.075 mmol) in DMF (1.0mL) at room temperature under argon was added DIEA (0.042 mL, 0.240mmol), followed by HATU (37.1 mg, 0.097 mmol). The reaction was allowedto stir for 5 min before Compound 2 (25.6 mg, 0.090 mmol) was added. Thereaction was allowed to stir at room temperature for 16 h, then dilutedwith water (10 ml) and extracted with EtOAc (3×10 ml)—brine was added toclear. The combined organic layer was washed with brine (10 ml), dried(MgSO₄) and concentrated in vacuo. Co-evaporation with heptane was usedto remove remaining traces of DMF. Purification by column chromatographyusing a gradient of 10% to 80% EtOAc/DCM gave the title compound as apale yellow solid (32 mg, 63%). ¹H NMR (500 MHz, Chloroform-d) δ 8.11(d, J=2.1 Hz, 1H), 7.89 (s, 1H), 7.79 (t, J=7.6 Hz, 2H), 7.74 (dd,J=8.2, 2.2 Hz, 1H), 7.70 (s, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.56 (dd,J=11.6, 7.5 Hz, 2H), 7.50-7.37 (m, 5H), 7.36-7.30 (m, 2H), 7.24 (d,J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 4.74 (dd, J=10.8, 5.7 Hz, 1H),4.68 (dd, J=10.8, 5.8 Hz, 1H), 4.56-4.49 (m, 1H), 4.35-4.27 (m, 5H),2.83-2.75 (m, 1H), 2.71-2.64 (m, 1H), 2.34 (s, 3H), 2.19-2.12 (m, 1H),1.62-1.53 (m, 1H), 1.09 (d, J=6.6 Hz, 2H). HRMS (ESI⁺): calcd forC₄₂H₃₇N₃O₆ (M+H)⁺, 680.2761; found 680.2740.

Example 152,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a stirring solution of Compound 192 (32 mg, 0.047 mmol) in DMF (1.0mL) was added piperidine (0.05 mL, 0.505 mmol). The reaction was allowedto stir at room temperature for 21 h. Further piperidine (0.05 mL, 0.505mmol) was added and the reaction stirred for 26 h. The reaction wasdiluted with water (15 ml) and extracted with EtOAc (2×15 ml). Thecombined organic layer was washed with brine (15 ml), dried (Na₂SO₄) andconcentrated in vacuo. Purification by biotage chromatography using agradient of 8% to 48% EtOAc/DCM gave the title compound as a white solid(16 mg, 74.3%). ¹H NMR (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.34 (s, 1H),7.77 (d, J=2.2 Hz, 1H), 7.56 (s, 1H), 7.55-7.54 (m, 1H), 7.53 (d, J=2.1Hz, 1H), 7.50 (dd, J=8.4, 2.2 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 6.97 (d,J=8.4 Hz, 1H), 6.49 (d, J=8.2 Hz, 1H), 6.28 (s, 1H), 4.35-4.25 (m, 4H),3.42-3.36 (m, 1H), 2.81-2.66 (m, 2H), 2.16 (s, 3H), 1.92-1.86 (m, 1H),1.49-1.39 (m, 1H), 1.17 (d, J=6.3 Hz, 3H). HRMS (ESI⁺): calcd forC₂₇H₂₇N₃O₄ (M+H)⁺, 458.2060; found 458.2074.

Preparation of Compound 193, 6-bromo-2-(1-methoxyethyl)quinoline

To a stirring solution of Compound 163 (75 mg, 0.297 mmol) in dry DMF (3mL) at 0° C. under argon was added sodium hydride (14.28 mg, 0.357mmol). The reaction was allowed to warm gradually to room temperatureover 40 min, then cooled back to 0° C. and iodomethane (0.093 mL, 1.487mmol) was added drop-wise. The reaction was allowed to warm to roomtemperature and left to stir for 2 days. The reaction was cooled back to0° C. and a further portion of sodium hydride (14.28 mg, 0.357 mmol) andiodomethane (0.093 mL, 1.487 mmol) added following the same procedure aspreviously. The flask was allowed to warm to room temperature and leftto stir for 5 h. The reaction was diluted with water (25 ml) andextracted with EtOAc (3×15 ml)—brine was added to clear. The combinedorganic layer was washed with brine (25 ml), dried (Na₂SO₄) andconcentrated in vacuo to afford the crude product as a yellow oil (45mg, 57%). ¹H NMR (500 MHz, Chloroform-d) δ 8.13 (d, J=8.6 Hz, 1H), 8.01(d, J=2.2 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.80 (dd, J=9.0, 2.2 Hz, 1H),7.63 (d, J=8.6 Hz, 1H), 4.61 (q, J=6.6 Hz, 1H), 3.36 (s, 3H), 1.56 (d,J=6.6 Hz, 3H). HRMS (ESI⁺): calcd for C₁₂H₁₃ ⁷⁹BrNO (M+H)⁺, 266.0181;found 266.0174.

Preparation of Compound 194, 2-(1-methoxyethyl)quinoline-6-carboxylicacid

To a stirring solution of Compound 193 (40 mg, 0.150 mmol) in dry THF (1mL) at −78° C. was drop-wise added freshly titrated n-BuLi (0.150 mL,0.331 mmol). The reaction was allowed to stir at −78° C. for 40 minbefore solid CO₂ was added. The reaction was left to stir at −78° C. for30 min before being allowed to warm to room temperature over 2 h. Thereaction mixture was diluted with water (15 ml) and the aqueous layeracidified with 1 M HCl aq. (to ˜pH 2/3) and the aqueous layer wasextracted with DCM (3×10 ml). The combined organic layer was dried(MgSO₄) and concentrated in vacuo to afford the title compound as anorange oil. This material was used directly in the next reaction withoutfurther purification. HRMS (ESI⁺): calcd for C₁₃H₁₄NO₃ (M+H)⁺, 232.0974;found 232.0975.

Example 153,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(1-methoxyethyl)quinoline-6-carboxamide

To a stirring solution of Compound 194 (35 mg, 0.151 mmol) in DMF (1.5mL) at room temperature under argon was added DIEA (0.058 mL, 0.333mmol), followed by HATU (74.8 mg, 0.197 mmol). The reaction was allowedto stir for 5 min before Compound 2 (51.6 mg, 0.182 mmol) was added. Thereaction was allowed to stir at room temperature for 7 h. Further DIEA(0.058 mL, 0.333 mmol), followed by HATU (74.8 mg, 0.197 mmol) andCompound 2 (51.6 mg, 0.182 mmol) was added and allowed to stir for 18 h,then the reaction mixture was heated to 40° C. for 23 h. The reactionwas diluted with water (15 ml) and extracted with EtOAc (3×15 ml)—brinewas added to clear. The combined organic layer was washed with brine (15ml), dried (Na₂SO₄) and concentrated in vacuo. Remaining traces of DMFwere removed by co-evaporation with heptane. An initial attempt topurify the crude product by biotage chromatography using a gradient of 0to 20% EtOAc/DCM failed. Therefore the material was purified by 2×preparative HPLC to afford the title compound as a formate salt (formicacid was used in the HPLC solvent system). The free amine was obtainedvia SCX chromatography eluting with MeOH, then 10% 2M NH₃ in MeOH toafford the title compound as a pale yellow solid (7 mg, 9%). ¹H NMR (500MHz, Methanol-d4) δ 8.63 (d, J=1.7 Hz, 1H), 8.56 (d, J=8.6 Hz, 1H),8.34-8.32 (m, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.82 (d, J=2.1 Hz, 1H), 7.77(d, J=8.5 Hz, 1H), 7.56 (dd, J=8.3, 2.2 Hz, 1H), 7.51-7.47 (m, 2H), 7.33(d, J=8.4 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 4.66 (q, J=6.6 Hz, 1H),4.35-4.29 (m, 4H), 3.37 (s, 3H), 2.36 (s, 3H), 1.56 (d, J=6.6 Hz, 3H).HRMS (ESI⁺): calcd for C₂₉H₂₈N₃O₅(M+H)⁺, 498.2006; found 498.2023.

Example 154,(S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a stirring suspension of Example 39 (124 mg, 0.273 mmol) in ethanol(9.6 mL) and ethyl acetate (7.2 mL) was added 10 drops glacial AcOH. Thereaction was flushed with argon and 10% Pd on activated carbon (60 mg,0.273 mmol) was added. The reaction flask was flushed with H₂, heated to50° C. and left to stir under 1 atm. H₂ for 24 h. Further glacial AcOH(5 drops) was added and the reaction allowed to stir for 48 h. Thereaction mixture was filtered through celite and the filtrateconcentrated in vacuo. The resulting residue was purified by columnchromatography using a gradient of 13 to 25% EtOAc/DCM to afford theracemic product as an off-white solid (69 mg). This material was thenseparated into individual enantiomers by chiral HPLC to afford the titlecompound as a pale yellow solid (11 mg, 9%). ¹H NMR (500 MHz, DMSO-d6) δ10.01 (s, 1H), 9.34 (s, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.56 (s, 1H),7.55-7.54 (m, 1H), 7.53 (d, J=2.1 Hz, 1H), 7.50 (dd, J=8.4, 2.2 Hz, 1H),7.17 (d, J=8.5 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.49 (d, J=8.2 Hz, 1H),6.28 (s, 1H), 4.35-4.25 (m, 4H), 3.42-3.36 (m, 1H), 2.81-2.66 (m, 2H),2.16 (s, 3H), 1.92-1.86 (m, 1H), 1.49-1.39 (m, 1H), 1.17 (d, J=6.3 Hz,3H). HRMS (ESI⁺): calcd for C₂₇H₂₈N₃O₄ (M+H)⁺, 458.2074; found 458.2058.As measured by chiral HPLC 95.7% pure, >99% ee. Absolute stereochemistryunknown.

Example 155,(R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

Following the same procedure outlined for Example 154, the oppositeenantiomer was also isolated by chiral HPLC to afford the title compoundas a pale yellow solid (11 mg, 9%). ¹H NMR (500 MHz, DMSO-d6) δ 10.01(s, 1H), 9.34 (s, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.56 (s, 1H), 7.55-7.54(m, 1H), 7.53 (d, J=2.1 Hz, 1H), 7.50 (dd, J=8.4, 2.2 Hz, 1H), 7.17 (d,J=8.5 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.49 (d, J=8.2 Hz, 1H), 6.28 (s,1H), 4.35-4.25 (m, 4H), 3.42-3.36 (m, 1H), 2.81-2.66 (m, 2H), 2.16 (s,3H), 1.92-1.86 (m, 1H), 1.49-1.39 (m, 1H), 1.17 (d, J=6.3 Hz, 3H). HRMS(ESI⁺): calcd for C₂₇H₂₈N₃O₄ (M+H)⁺, 458.2074; found 458.2055. Asmeasured by chiral HPLC 99% pure, 97.4% ee. Absolute stereochemistryunknown.

Preparation of Compound 195,6-bromo-3-(2-(pyrrolidin-1-yl)ethoxy)isoquinoline

To a stirring suspension of sodium hydride (142 mg, 3.56 mmol) inanhydrous THF (10 mL) at 0° C. under argon was drop-wise added1-(2-hydroxyethyl)pyrrolidine (0.434 mL, 3.71 mmol). The reaction wasallowed to stir at 0° C. for 10 min, then allowed to warm to roomtemperature over 30 min. 6-Bromo-3-chloroisoquinoline (750 mg, 3.09mmol) was added and the reaction heated to 70° C. for 18 h. The reactionwas diluted with sat. NaHCO₃ aq. (30 ml) and the THF removed in vacuo.The aqueous layer was extracted with EtOAc (3×20 ml). The combinedorganic layer was washed with brine (20 ml), dried (Na₂SO₄) andconcentrated in vacuo. Purification by biotage chromatography using agradient of 3 to 30% MeOH/DCM afforded the title compound as a waxybrown solid (300 mg, 30%). ¹H NMR (500 MHz, Chloroform-d) δ 8.90 (s,1H), 7.87 (d, J=1.4 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8,1.8 Hz, 1H), 6.96 (s, 1H), 4.57 (t, J=5.8 Hz, 2H), 3.03 (t, J=5.8 Hz,2H), 2.79-2.73 (m, 4H), 1.89-1.85 (m, 4H). HRMS (ESI⁺): calcd for C₁₅H₁₈⁷⁹BrN₂O (M+H)⁺, 321.0603; found 321.0597.

Example 156,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-3-(2-(pyrrolidin-1-yl)ethoxy)isoquinoline-6-carboxamide

Tetraethylammonium chloride (25.8 mg, 0.156 mmol) and molybdenumhexacarbonyl (41.1 mg, 0.156 mmol) were combined in anhydrous dioxane(0.5 mL). The reaction was heated to 140° C. for 2 min to form theactive catalyst. Compound 2 (89 mg, 0.311 mmol) and Example 155 (50 mg,0.156 mmol) were then added and the reaction heated to 130° C. for 4 hin a MW. The reaction mixture was taken up in a mixture of EtOAc andMeOH and the solvents removed in vacuo to afford a black solid. Thecrude material was taken up in DCM/MeOH and dry-loaded onto silica.Purification by column chromatography using a gradient of 2 to 10%MeOH/DCM afforded the title compound as a yellow solid (24 mg, 28%). ¹HNMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 10.10 (s, 1H), 9.21 (s, 1H),8.49 (s, 1H), 8.21 (d, J=8.7 Hz, 1H), 7.96 (dd, J=8.6, 1.3 Hz, 1H), 7.90(d, J=2.0 Hz, 1H), 7.58 (dd, J=8.3, 2.2 Hz, 1H), 7.55 (d, J=2.1 Hz, 1H),7.52 (dd, J=8.4, 2.2 Hz, 1H), 7.42 (s, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.99(d, J=8.4 Hz, 1H), 4.63 (t, J=4.9 Hz, 3H), 4.35-4.29 (m, 4H), 3.18-3.06(m, 4H), 2.25 (s, 3H), 1.93-1.85 (m, 4H) (Note: 1 CH₂ hidden under waterpeak). HRMS (ESI⁺): calcd for C₃₂H₃₃N₄O₅ (M+H)⁺, 553.2445; found553.2435.

Preparation of Compound 196, ethyl 5-allylquinoline-3-carboxylate

Tetrakis(triphenylphosphine) palladium(O) (1165 mg, 1.008 mmol) wasadded to a stirring, degassed (3× vacuum/argon cycles) solution of ethyl5-chloroquinoline-3-carboxylate (950 mg, 4.03 mmol), allyltributylstannane (3.75 mL, 12.09 mmol) and lithium chloride (514 mg,12.09 mmol) in DMF (40 mL) and the reaction heated to 110° C. for 23 h.The reaction mixture was concentrated under high vacuum to remove mostof the DMF. The residue was then poured into water (100 ml) andextracted with EtOAc (50 ml). The organic layer was washed with water(50 ml), brine (50 ml) and dried (Na₂SO₄). Purification by columnchromatography using a gradient of 0 to 40% EtOAc/cyclohexane affordedthe title compound as a yellow oil (520 mg, 54%). ¹H NMR (500 MHz,Chloroform-d) δ 9.45 (d, J=2.0 Hz, 1H), 9.07 (dd, J=2.0, 0.8 Hz, 2H),8.06 (d, J=8.5 Hz, 1H), 7.77 (dd, J=8.5, 7.1 Hz, 1H), 7.49 (d, J=6.7 Hz,1H), 6.11 (ddt, J=16.5, 10.2, 6.3 Hz, 1H), 5.18 (dq, J=10.1, 1.4 Hz,2H), 5.10 (dq, J=17.1, 1.6 Hz, 1H), 4.50 (q, J=7.1 Hz, 2H), 3.91 (d,J=6.2 Hz, 3H), 1.48 (t, J=7.1 Hz, 3H).

Preparation of Compound 197, ethyl5-(2,3-dihydroxypropyl)quinoline-3-carboxylate

To a stirring solution of compound 196 (397 mg, 1.645 mmol) and osmiumtetroxide (20.91 mg, 0.082 mmol) in acetone (14 mL) and water (1.4 mL)was added NMO (N-Methyl morpholine N-oxide) (289 mg, 2.468 mmol). Thereaction was left to stir for 18 h. Saturated sodium sulfate aq. wasadded to the solution (10 ml) and the reaction allowed to stir for 1.5h. A precipitate formed. The aqueous layer was extracted with EtOAc(3×30 ml) and the combined organic layer washed with brine (20 ml),dried (Na₂SO₄) and concentrated in vacuo to afford the title compound asa yellow semi-solid (282 mg, 62%). This material was used as crudedirectly in the next reaction. HRMS (ESI⁺): calcd for C₅H₁₇NO₄ (M+H)⁺,276.1236; found 276.1248.

Preparation of Compound 198, ethyl 5-(2-oxoethyl)quinoline-3-carboxylate

To a stirring solution of Compound 197 (277 mg, 1.006 mmol) in MeOH (8.6mL) and THF (3.5 mL) at 0° C. was added a solution of sodium periodate(323 mg, 1.509 mmol) in water (8.60 mL). The reaction was allowed towarm to room temperature and left to stir for 1.25 h. The reaction wasdiluted with EtOAc (50 ml), washed with water (30 ml)—brine was added toclear, extracted with a further portion of EtOAc (30 ml). The combinedorganic layer was washed with brine (30 ml), dried (Na₂SO₄) andconcentrated in vacuo to afford the crude product as a yellow oil (245mg, 100%). ¹H NMR (500 MHz, Chloroform-d) δ 9.89 (t, J=1.9 Hz, 1H), 9.49(d, J=2.0 Hz, 1H), 8.89 (dd, J=1.9, 0.8 Hz, 1H), 8.17 (d, J=8.5 Hz, 2H),7.83 (dd, J=8.5, 7.1 Hz, 1H), 7.54 (d, J=7.0 Hz, 1H), 4.51 (q, J=7.1 Hz,2H), 4.25 (d, J=1.8 Hz, 2H), 1.48 (t, J=7.2 Hz, 3H). HRMS (ESI⁺): calcdfor C₁₄H₁₄NO₄ (M+H)⁺, 244.0794; found 244.0972.

Preparation of Compound 199, ethyl5-(2-hydroxypropyl)quinoline-3-carboxylate

To a stirring solution of Compound 198 (245 mg, 1.007 mmol) in ethanol(6.5 mL) and water (3.25 mL) at 0° C. was added sodium borohydride (191mg, 5.04 mmol) and the reaction left to stir at 0° C. for 2.5 h. Thereaction mixture was diluted with water (30 ml), and extracted withEtOAc (2×25 ml)—brine was added to clear. The combined organic layer waswashed with brine (20 ml), dried (Na₂SO₄) and concentrated in vacuo.Purification by biotage chromatography using a gradient of 6 to 80%EtOAc/DCM afforded the title compound as a pale orange solid (99 mg,40%). ¹H NMR (500 MHz, Chloroform-d) δ 9.42 (d, J=2.0 Hz, 1H), 9.09 (dd,J=2.0, 0.8 Hz, 2H), 8.03 (d, J=8.5 Hz, 1H), 7.76 (dd, J=8.5, 7.1 Hz,1H), 7.55 (br d, J=7.0 Hz, 1H), 4.52 (q, J=7.1 Hz, 2H), 4.05 (t, J=6.4Hz, 2H), 3.51 (s, 1H, OH), 3.43 (t, J=6.6 Hz, 2H), 1.49 (t, J=7.1 Hz,3H). HRMS (ESI⁺): calcd for C₁₄H₁₆NO₃ (M+H)⁺, 246.1130; found 246.1142.

Preparation of Compound 200, ethyl5-(2-((tert-butyldimethylsilyl)oxy)ethyl)quinoline-3-carboxylate

To a solution of Compound 199 (89 mg, 0.363 mmol) in anhydrous DCM (3.5mL) was added imidazole (37.1 mg, 0.544 mmol) followed bytert-butyldimethylsilyl chloride (62.9 mg, 0.417 mmol). The reaction wasstirred at room temperature for 2 h, then diluted with DCM (10 mL) andwashed with water (1×10 mL), 0.25 M HCl (1×10 mL), brine (1×10 mL),dried (MgSO₄) and concentrated in vacuo. Purification by biotagechromatography using a gradient of 2 to 20% EtOAc/cyclohexane gave thetitle compound as a colourless oil (33 mg, 25%). ¹H NMR (500 MHz,Chloroform-d) δ 9.44 (d, J=2.0 Hz, 1H), 9.10 (dd, J=2.0, 0.8 Hz, 2H),8.04 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.5, 7.1 Hz, 1H), 7.49 (d, J=6.5 Hz,1H), 4.49 (q, J=7.1 Hz, 2H), 3.94 (t, J=6.7 Hz, 2H), 3.34 (t, J=6.7 Hz,2H), 1.47 (t, J=7.1 Hz, 3H), 0.80 (s, 9H), −0.10 (s, 6H). HRMS (ESI⁺):calcd for C₂₀H₃₀NO₃Si (M+H)⁺, 360.1995; found 360.2009.

Preparation of Compound 201,5-(2-((tert-butyldimethylsilyl)oxy)ethyl)quinoline-3-carboxylic acid

To a stirring solution of Compound 200 (30 mg, 0.083 mmol) in THF (0.6mL) and MeOH (0.2 mL) was added a solution of 2M NaOH aq. (0.083 mL,0.167 mmol). The reaction was left to stir for 15.5 h, then diluted withwater (15 ml) and the solution made acidic by the addition of 1 M HClaq. (to ˜pH 3). The aqueous layer was extracted with EtOAc (2×15 ml).The combined organic layer was washed with water (15 ml), brine (15 ml)and dried (Na₂SO₄), then concentrated in vacuo to afford the titlecompound as a white solid (25.5 mg, 92%). ¹H NMR (500 MHz, Chloroform-d)δ 9.59 (s, 1H), 9.29 (s, 1H), 8.17 (d, J=8.4 Hz, 1H), 7.83 (dd, J=8.4,7.1 Hz, 1H), 7.56 (d, J=6.9 Hz, 1H), 4.00 (t, J=6.6 Hz, 2H), 3.40 (t,J=6.6 Hz, 2H), 0.82 (s, 9H), −0.08 (s, 6H). HRMS (ESI⁺): calcd forC₁₈H₂₅NO₃Si (M+H)⁺, 332.1682; found 332.1680.

Preparation of Compound 202,5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-3-carboxamide

To a stirring solution of Compound 201 (23 mg, 0.069 mmol) in DMF (0.7mL) at room temperature under argon was added DIEA (0.039 mL, 0.222mmol), followed by HATU (34.3 mg, 0.090 mmol). The reaction was allowedto stir for 5 min before Compound 2 (23.67 mg, 0.083 mmol) was added.The reaction was allowed to stir at room temperature for 15.5 h, thenpoured into water (20 ml) and extracted with EtOAc (20 ml)—brine wasadded to clear. The organic layer was washed with a further portion ofbrine (20 ml), dried (Na₂SO₄) and concentrated in vacuo to afford ayellow oil. Purification by column chromatography using a gradient of 10to 50% EtOAc/DCM gave the title compound as a pale yellow foam (34 mg,82%). ¹H NMR (500 MHz, Chloroform-d) δ 9.36 (d, J=2.0 Hz, 1H), 9.02-8.99(br s, 1H), 8.13-8.11 (br s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.98 (s, 1H),7.85 (s, 1H), 7.76 (dd, J=8.5, 7.1 Hz, 1H), 7.66 (dd, J=8.3, 2.2 Hz,1H), 7.53 (br d, J=7.1 Hz, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.37 (dd, J=8.4,2.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.35-4.26(m, 4H), 3.97 (t, J=6.5 Hz, 2H), 3.35 (t, J=6.5 Hz, 2H), 2.35 (s, 3H),0.77 (s, 9H), −0.14 (s, 6H). HRMS (ESI⁺): calcd for C₃₄H₄₀N₃O₅Si (M+H)⁺,598.2737; found 598.2715.

Example 157,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-5-(2-hydroxyethyl)quinoline-3-carboxamide

To a stirring solution of Compound 202 (31 mg, 0.052 mmol) in THF (1.5mL) at room temperature under argon was slowly added TBAF (1M in THF,0.078 mL, 0.078 mmol). The reaction was allowed to stir for 3.75 h. Thereaction was diluted with water (20 ml) and the resulting precipitatewas collected by filtration, washed with water and dried under vacuum toafford the title compound as a white solid (9 mg, 36%). ¹H NMR (500 MHz,DMSO-d6) δ 10.36 (s, 1H), 10.10 (s, 1H), 9.39 (d, J=1.8 Hz, 1H), 9.15(s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.82 (dd,J=8.4, 7.2 Hz, 1H), 7.64-7.58 (m, 2H), 7.55 (d, J=2.1 Hz, 1H), 7.53 (dd,J=8.4, 2.1 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 4.82(t, J=5.3 Hz, 1H), 4.35-4.29 (m, 4H), 3.79 (q, J=6.7 Hz, 2H), 2.27 (s,3H). HRMS (ESI⁺): calcd for C_(2s)H₂₆N₃O₅ (M+H)⁺, 484.1867; found484.1851.

Preparation of Compound 203, ethyl5-(2-(pyrrolidin-1-yl)ethyl)quinoline-3-carboxylate

To a stirring solution of Compound 198 (45 mg, 0.185 mmol) in CHCl₃ (2mL) at room temperature under nitrogen was added acetic acid (10.58 μL,0.185 mmol), followed by pyrrolidine (0.020 mL, 0.240 mmol). Sodiumtriacetoxyborohydride (43.1 mg, 0.203 mmol) was then added and thereaction left to stir at room temperature for 16.5 h. The reaction wasdiluted with CHCl₃ (30 ml) and washed with brine (20 ml). The aqueouslayer was extracted with a further portion of CHCl₃ (20 ml) and thecombined organic layer dried (Na₂SO₄) and concentrated in vacuo.Purification by column chromatography using a gradient of 2 to 10%MeOH/DCM+2% 2M NH₃ in MeOH gave the title compound as a yellow oil (10mg, 18%). ¹H NMR (500 MHz, Chloroform-d) δ 9.46 (d, J=2.0 Hz, 1H),9.10-9.08 (m, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.77 (dd, J=8.5, 7.2 Hz, 1H),7.57 (d, J=7.0 Hz, 1H), 4.51 (q, J=7.2 Hz, 2H), 3.61-3.54 (m, 2H),3.15-3.06 (m, 3H), 3.05-2.95 (s, 4H), 2.04-2.00 (m, 4H), 1.49 (t, J=7.1Hz, 3H). HRMS (ESI⁺): calcd for C₁₈H₂₂N₂O₂ (M+H)⁺, 299.1760; found299.1757.

Example 158,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-5-(2-(pyrrolidin-1-yl)ethyl)quinoline-3-carboxamide

To a stirring solution of Compound 203 (10 mg, 0.034 mmol) in THF (0.3mL) and MeOH (0.1 mL) was added 2M NaOH aq. (0.034 mL, 0.067 mmol). Thereaction was left to stir at room temperature for 17.5 h, then thesolvents were removed in vacuo. The resulting residue was taken up inwater (15 ml) and made acidic using 1M HCl aq. (to ˜pH 3). The organiclayer was washed with EtOAc (10 ml) and the aqueous layer wasconcentrated in vacuo to afford5-(2-(pyrrolidin-1-yl)ethyl)quinoline-3-carboxylic acid as a brownsolid. To a stirring solution of5-(2-(pyrrolidin-1-yl)ethyl)quinoline-3-carboxylic acid (11 mg, 0.036mmol) in DMF (0.4 mL) at room temperature under argon was added DIEA(0.026 mL, 0.151 mmol), followed by HATU (17.72 mg, 0.047 mmol). Thereaction was allowed to stir for 5 min before Compound 2 (11.21 mg,0.039 mmol) was added. The reaction was allowed to stir for 24 h.Further HATU (17.72 mg, 0.047 mmol) and DIEA (0.026 mL, 0.151 mmol) wereadded and the reaction left to stir for a 5.5 h. The reaction mixturewas diluted with water (20 ml) and extracted with EtOAc (2×20 ml)—brinewas added to clear. The combined organic layer was washed with brine (20ml), dried (Na₂SO₄) and concentrated in vacuo. Purification by columnchromatography using a gradient of 0 to 10% MeOH/DCM+0.5% 2M NH₃ in MeOHgave the title compound as a yellow glass (8 mg, 42%). ¹H NMR (500 MHz,DMSO-d6) δ 10.34 (s, 1H), 10.10 (s, 1H), 9.41 (br s, 1H), 9.12 (br s,1H), 8.04 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.88-7.83 (m, 1H), 7.66 (d,J=7.1 Hz, 1H), 7.55-7.47 (m, 3H), 7.27 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 4.34-4.28 (m, 4H), 3.58-3.46 (m, 2H), 2.94-2.86 (m, 2H), 2.28(s, 3H) 2.00-1.80 (4H, m). Note: 4H under H₂O peak. HRMS (ESI⁺): calcdfor C₃₂H₃₂N₄O₄ (M+H)*, 537.2502; found 537.2485.

Example 159,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1,2-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a stirring suspension of Example 39 (125 mg, 0.276 mmol) in MeOH (9.6mL) and ethyl acetate (7.2 mL) was added glacial AcOH (10 drops). Thereaction mixture was sonicated and to dissolve all solids. The flask wasflushed with argon and 10% Pd on activated carbon (0.060 g, 0.276 mmol)was added. The flask was then purged with H₂ and the reaction heated to40° C. under 1 atm H₂ for 4 days. Over this time period two furtherportions of 10% Pd on activated carbon (0.060 g, 0.276 mmol) and glacialAcOH (5 drops) were added to drive the reaction to completion. Thereaction mixture was filtered through celite and concentrated in vacuo.Purification by biotage chromatography using a gradient of 6 to 100%EtOAc/DCM afforded the title compound as a white solid (25 mg, 19%). ¹HNMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.44 (s, 1H), 7.78 (d, J=2.1 Hz,1H), 7.72 (dd, J=8.6, 2.2 Hz, 1H), 7.63 (d, J=1.9 Hz, 1H), 7.57-7.53 (m,3H), 7.52 (d, J=2.2 Hz, 1H), 7.51 (dd, J=8.4, 2.2 Hz, 1H), 7.19 (d,J=8.5 Hz, 1H) 6.99 (d, J=8.4 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 4.35-4.28(m, 4H), 3.58-3.52 (m, 1H), 2.94 (s, 3H), 2.88-2.79 (m, 1H), 2.74-2.67(m, 1H), 2.18 (s, 3H), 1.92-1.74 (m, 2H), 1.12 (d, J=6.5 Hz, 3H). HRMS(ESI⁺): calcd for C₂₈H₃₀N₃O₄ (M+H)⁺, 472.2231; found 472.2210.

Example 160,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-8-(2-methoxyethoxy)quinoline-6-carboxamide

To a stirring suspension of NaH (55.8 mg, 1.395 mmol) in NMP (2.0 mL) ina microwave vial at 0° C. under argon was slowly added 2-methoxyethanol(0.114 mL, 1.456 mmol). The reaction was allowed to warm slowly to roomtemperature over 1 h. Compound 153 (100 mg, 0.404 mmol) was added andthe reaction mixture heated to 140° C. for 15 min. The reaction wasdiluted with water (30 ml) and acidified with 1 M HCl aq. (to ˜pH 3).The aqueous layer was extracted with DCM (3×15 ml) and the combinedorganic layer washed with water (2×15 ml), dried (Na₂SO₄) andconcentrated in vacuo to afford the crude product as a yellow oil. Thecrude material was purified by SCX chromatography (eluting with MeOHthen 10% 2M NH₃ in MeOH) to afford8-(2-methoxyethoxy)quinoline-6-carboxylic acid as a pale yellow solid.HATU (200 mg, 0.525 mmol) was added to a stirring solution of8-(2-methoxyethoxy)quinoline-6-carboxylic acid (100 mg, 0.404 mmol) andDIEA (0.225 mL, 1.293 mmol) in DMF (4.0 mL) at room temperature underargon. The reaction was allowed to stir for 5 min before Compound 2 (115mg, 0.404 mmol) was added. The reaction was allowed to stir at roomtemperature for 22 h, then diluted with water (30 ml) and extracted withEtOAc (3×15 ml)—brine was added to clear. The combined organic layer waswashed with brine (2×20 ml), dried (Na₂SO₄) and concentrated in vacuo.Purification by column chromatography using a gradient of 20 to 50%EtOAc/DCM, then 10% MeOH/DCM gave the title compound as a pale yellowsolid (41 mg, 20%). ¹H NMR (500 MHz, Methanol-d4) δ 8.92 (dd, J=4.3, 1.7Hz, 1H), 8.47 (dd, J=8.4, 1.6 Hz, 1H), 8.18 (d, J=1.4 Hz, 1H), 7.81 (d,J=2.2 Hz, 1H), 7.73 (br s, 1H), 7.66 (dd, J=8.3, 4.3 Hz, 1H), 7.52 (dd,J=8.3, 2.2 Hz, 1H), 7.48-7.44 (m, 2H), 7.29 (d, J=8.4 Hz, 1H), 6.93 (d,J=8.4 Hz, 1H), 4.48-4.44 (m, 2H), 4.32-4.26 (m, 4H), 3.99-3.95 (m, 2H),3.48 (s, 3H), 2.32 (s, 3H). HRMS (ESI⁺): calcd for C₂₉H₂₈N₃O₆ (M+H)⁺,514.1973; found 514.1965.

Preparation of Compound 204, 5-allylquinoline-3-carboxylic acid

To a stirring solution of Compound 196 (73 mg, 0.303 mmol) in THF (1.8mL) and MeOH (0.6 mL) was added 2M NaOH aq. (0.303 mL, 0.605 mmol). Thereaction was allowed to stir at room temperature for 19 h, then thesolvents were removed in vacuo. The resulting residue was taken up inwater (25 ml) and acidified with 1 M HCl aq. (to ˜pH2/3). The aqueouslayer was extracted with EtOAc (2×20 ml) and the organic layer waswashed with 1 M NaOH (2×20 ml) and once with water (10 ml). The combinedaqueous layer was acidified (to ˜pH 2/3) and extracted with EtOAc (2×20ml). The combined organic layer was washed with brine (20 ml) and dried(Na₂SO₄) to afford the title compound as a yellow/brown oil (32 mg,50%). This material was used without any further purification. HRMS(ESI⁺): calcd for C₁₃H₁₂NO (M+H)⁺, 214.0868; found 214.0866.

Example 161,5-allyl-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-3-carboxamide

To a stirring solution of Compound 204 (29 mg, 0.136 mmol) in DMF (1.2mL) at room temperature under argon was added DIEA (0.047 mL, 0.272mmol), followed by HATU (61.1 mg, 0.161 mmol). The reaction was allowedto stir for 5 min before Compound 2 (35.2 mg, 0.124 mmol) was added. Thereaction was allowed to stir for 18.5 h, then diluted with water and theresulting precipitate collected by filtration and washed with water. Thesample was air dried for 1 h, then dried under vacuum to afford thetitle compound as a beige solid (39 mg, 66%). ¹H NMR (500 MHz, DMSO-d6)δ 10.34 (s, 1H), 10.10 (s, 1H), 9.41 (d, J=1.7 Hz, 1H), 9.12 (br s, 1H),8.01 (d, J=8.4 Hz, 1H), 7.94-7.91 (m, 1H), 7.84 (dd, J=8.3, 7.2 Hz, 1H),7.63-7.51 (m, 5H), 7.28 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H),6.21-6.11 (m, 1H), 5.16-5.10 (m, 2H), 4.35-4.29 (m, 4H), 4.00-3.96 (m,2H), 2.27 (s, 3H). HRMS (ESI⁺): calcd for C_(2s)H₂₆N₃O₄ (M+H)⁺,480.1918; found 480.1895.

Preparation of Compound 205, butyl8-((2-(dimethylamino)ethyl)(methyl)amino)quinoline-6-carboxylate

To a stirring solution of Compound 153 (119 mg, 0.481 mmol) in anhydrousNMP (3.0 mL) was added N,N,N′-trimethylenediamine (0.320 mL, 2.406mmol). The reaction was heated to 140° C. in a microwave for 10.75 h.The reaction mixture was partitioned between EtOAc (30 ml) and sat.NaHCO₃ aq. (30 ml). The aqueous layer was extracted with further EtOAc(2×20 ml) and the combined organic layer was washed with water (2×20ml), brine (20 ml), dried Na₂SO₄ and concentrated in vacuo to afford thecrude product as a yellow/brown oil. Purification by columnchromatography using a gradient of 5 to 10% MeOH/DCM+5% 2M NH₃ in MeOHgave the title compound as a yellow oil (60 mg, 38%). ¹H NMR (500 MHz,Chloroform-d) b 8.96-8.92 (m, 1H), 8.21 (dd, J=8.3, 1.8 Hz, 1H), 8.11(d, J=1.7 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.44 (dd, J=8.3, 4.2 Hz, 1H),4.40 (t, J=6.7 Hz, 2H), 3.76-3.67 (m, 2H), 3.12 (s, 3H), 2.75-2.66 (m,2H), 2.29 (s, 3H), 1.85-1.79 (m, 2H), 1.58-1.49 (m, 2H), 1.03 (t, J=7.4Hz, 4H). HRMS (ESI⁺): calcd for C₁₉H₂₈N₃O₂ (M+H)⁺, 330.2183; found330.2195.

Preparation of Compound 206,8-((2-(dimethylamino)ethyl)(methyl)amino)quinoline-6-carboxylic acidhydrochloride salt

A solution of Compound 205 (55 mg, 0.167 mmol) in 6M HCl aq. (1.0 mL,0.167 mmol) was heated to 80° C. for 5 h, after this time the startingmaterial had been consumed as indicated by LCMS. Therefore the solventswere removed in vacuo and remaining traces of water were removed byco-evaporation with MeCN, then toluene to afford the title compound as ayellow solid. This material was used in the next reaction withoutfurther purification. ¹H NMR (500 MHz, Methanol-d4) δ 9.33-9.28 (m, 2H),8.81 (br s, 1H), 8.45 (br s, 1H), 8.23-8.18 (m, 1H), 3.69 (t, J=5.6 Hz,1H), 3.61 (t, J=5.5 Hz, 1H), 2.95 (s, 6H), 2.94 (s, 3H). HRMS (ESI⁺):calcd for C₁₅H₂₀N₃O₂ (M+H)⁺, 274.1556; found 274.1555.

Example 162,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-8-((2-(dimethylamino)ethyl)(methyl)amino)quinoline-6-carboxamide

To a stirring solution of Compound 206 (51.7 mg, 0.167 mmol) in DMF (2.0mL) at room temperature under argon was added DIEA (0.151 mL, 0.868mmol), followed by HATU (82 mg, 0.217 mmol). The reaction was allowed tostir for 5 min before Compound 2 (47.4 mg, 0.167 mmol) was added. Thereaction was allowed to stir for 15.5 h. The reaction mixture waspartitioned between water (20 ml) and EtOAc (20 ml). Brine (10 ml) wasadded to the aqueous layer which was further extracted with EtOAc (2×20ml). The combined organic layer was washed with brine (20 ml), driedNa₂SO₄ and concentrated in vacuo. Traces of DMF were removed byco-evaporation with heptane, to afford the crude product as ayellow/brown oil. Purification by column chromatography using a gradientof 3 to 10% MeOH/DCM, then 10% MeOH/DCM+2 to 5% 2M NH₃ in MeOH gave thetitle compound as a pale orange solid (56 mg, 62%). ¹H NMR (500 MHz,DMSO-d6) δ 10.10 (s, 1H), 10.07 (s, 1H), 8.94-8.90 (m, 1H), 8.44 (d,J=8.3 Hz, 1H), 8.09 (s, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.62-7.55 (m, 3H),7.54 (d, J=2.1 Hz, 1H), 7.51 (dd, J=8.4, 2.1 Hz, 1H), 7.25 (d, J=8.4 Hz,1H), 6.98 (d, J=8.4 Hz, 1H), 4.34-4.28 (m, 4H), 3.75 (t, J=6.4 Hz, 2H),3.07 (s, 3H), 2.78 (m, 2H), 2.33 (br s, 6H), 2.24 (s, 3H). HRMS (ESI⁺):calcd for C₃₁H₃₃N₅O₄ (M+H)⁺, 541.2636; found 541.2628.

Preparation of Compound 207,3-((6-bromoquinolin-2-yl)(methyl)amino)propanenitrile

6-Bromo-2-chloroquinoline (250 mg, 1.031 mmol) and N-methyl-beta-alaninenitrile (0.482 mL, 5.15 mmol) in NMP (10 mL) were heated to 140° C. inthe microwave for 5 h. The reaction mixture was poured into sat. NaHCO₃aq. (50 ml) and extracted with EtOAc (3×50 ml)—further water and brinehad to be added in order to clear the aqueous layer. The combinedorganic layer was washed with water (2×50 ml), brine (50 ml) andconcentrated in vacuo to give a pale brown semi-solid. Purification bybiotage chromatography using a gradient of 5 to 40% MeOH/DCM gave thetitle compound as a yellow solid (193 mg, 32%). ¹H NMR (500 MHz,Chloroform-d) δ 7.86 (d, J=9.1 Hz, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.62(dd, J=8.9, 2.2 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 6.93 (d, J=9.1 Hz, 1H),4.05 (t, J=6.5 Hz, 2H), 3.31 (s, 3H), 2.86 (t, J=6.5 Hz, 2H). HRMS(ESI⁺): calcd for C₁₃H₁₃ ⁷⁹BrN₃ (M+H)⁺, 290.0287; found 290.0283.

Preparation of Compound 208, 2-(trimethylsilyl)ethyl2-((2-cyanoethyl)(methyl)amino)quinoline-6-carboxylate

To a stirring suspension of Compound 207 (100 mg, 0.345 mmol), Hermann'spalladacycle (16.2 mg, 0.017 mmol) and tri-t-butylphosphoniumtetrafluoroborate (20 mg, 0.069 mmol) in 2-(trimethylsilyl)-ethanol (3.0mL) was added molybdenum hexacarbonyl (182 mg, 0.689 mmol) followed byDBU (1.0M in THF, 1.03 ml, 1.03 mmol). The reaction mixture was heatedto 130° C. in a microwave for 1 h. The reaction mixture was diluted withEtOAc, filtered through celite and concentrated in vacuo. The crudereaction was loaded onto an SCX column and eluted with MeOH, 1% 2M NH₃in MeOH/MeOH, then 10% 2M NH₃ in MeOH/MeOH to afford a brown oil.Purification of this oil by biotage chromatography using a gradient of 5to 40% EtOAc/cyclohexane afforded the title compound as a white solid(84 mg, 69%). ¹H NMR (500 MHz, Chloroform-d) δ 8.40 (br s, 1H), 8.17 (d,J=8.6 Hz, 1H), 8.02 (d, J=9.1 Hz, 1H), 7.68 (s, 1H), 6.95 (d, J=9.1 Hz,1H), 4.54-4.39 (m, 2H), 4.13-4.05 (m, 2H), 3.34 (s, 3H), 2.94-2.84 (m,2H), 1.26-1.07 (m, 2H), 0.12 (s, 9H). HRMS (ESI⁺): calcd forC₁₉H₂₅N₃NaO₂Si (M+Na)+, 379.1632; found 379.1626.

Preparation of Compound 209,2-((2-cyanoethyl)(methyl)amino)quinoline-6-carboxylic acid

To a stirring solution of Compound 208 (81 mg, 0.228 mmol) in THF (2.5mL) at room temperature under argon was slowly added TBAF (1.0M in THF,0.342 mL, 0.342 mmol) and the reaction was allowed to stir for 20.5 h.Water (10 ml) was added and the reaction mixture concentrated to removeTHE. The aqueous layer was acidified using 1 M HCl aq. (to ˜pH 3) andextracted with EtOAc (3×15 ml)—brine was added to clear. The combinedorganic layer was washed with brine (10 ml), dried (Na₂SO₄) andconcentrated in vacuo to afford the title compound as a white solid (31mg, 53%). ¹H NMR (500 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.38 (d, J=2.0 Hz,1H), 8.21 (d, J=9.2 Hz, 1H), 8.00 (dd, J=8.7, 2.0 Hz, 1H), 7.58 (d,J=8.7 Hz, 1H), 7.21 (d, J=9.2 Hz, 1H), 3.99 (t, J=6.7 Hz, 2H), 3.23 (s,3H), 2.89 (t, J=6.7 Hz, 2H).

Preparation of Compound 210,2-((2-cyanoethyl)(methyl)amino)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide

To a stirring solution of Compound 209 (27 mg, 0.091 mmol) and DIEA(0.048 mL, 0.273 mmol) in DMF (1 mL) under argon was added HATU (41.5mg, 0.109 mmol). The reaction was allowed to stir for 3 min before theaddition of Compound 2 (31.0 mg, 0.109 mmol). The reaction was allowedto stir at room temperature for 22 h. The reaction mixture was pouredinto water (25 ml) and the aqueous layer extracted with EtOAc (3×15ml)—brine was added to clear. The combined organic layer was washed withbrine (15 ml) and dried (Na₂SO₄) to afford the crude product as a beigesolid. The solid was dry-loaded onto silica using DCM/MeOH and purifiedby column chromatography using a gradient of 0 to 10% EtOAc/DCM, then 5to 10% MeOH/DCM afforded the title compound as a beige solid (44 mg,93%). ¹H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.93 (s, 1H), 8.42 (d,J=2.0 Hz, 1H), 8.19 (d, J=9.1 Hz, 1H), 8.11 (dd, J=8.8, 2.1 Hz, 1H),7.85 (d, J=2.1 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.3, 2.2 Hz,1H), 7.54 (d, J=2.1 Hz, 1H), 7.51 (dd, J=8.5, 2.2 Hz, 1H), 7.23 (dd,J=8.8, 3.6 Hz, 2H), 6.98 (d, J=8.4 Hz, 1H), 4.33-4.28 (m, 4H), 4.01 (t,J=6.6 Hz, 2H), 3.24 (s, 3H), 2.91 (t, J=6.7 Hz, 2H), 2.23 (s, 3H). HRMS(ESI⁺): calcd for C₃₀H₂₈N₅O₄ (M+H)⁺, 522.2136; found 522.2140.

Example 163,3-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinolin-2-yl)(methyl)amino)propanoicacid

To a stirring solution of Compound 210 (20 mg, 0.038 mmol) in THF (0.6mL) was added hydrogen peroxide (35%, 0.3 mL, 0.038 mmol) and 1 M NaOHaq. (0.3 mL, 0.038 mmol). The reaction was allowed to stir at roomtemperature for 28.5 h. Further 1 M NaOH aq. (0.3 mL, 0.038 mmol) wasadded and left to stir for 2 more days. The reaction was diluted withwater (10 ml) and the aqueous layer washed with EtOAc (5 ml). Theaqueous layer was acidified using 1 M HCl aq. (to ˜pH 2) and extractedwith EtOAc (3×10 ml)—brine was added to clear. The combined organiclayer was washed with brine (10 ml), dried (Na₂SO₄) and concentrated invacuo to afford the product as a beige solid. This material wastriturated with ether to afford the title compound as a pale yellowsolid (1.6 mg, 8%). ¹H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.92 (s,1H), 8.39 (d, J=1.9 Hz, 1H), 8.14 (d, J=9.3 Hz, 1H), 8.10 (dd, J=8.7,2.0 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.59 (dd,J=8.1, 1.9 Hz, 1H), 7.55 (d, J=2.1 Hz, 1H), 7.52 (dd, J=8.4, 2.1 Hz,1H), 7.23 (d, J=8.5 Hz, 1H), 7.18 (d, J=9.2 Hz, 1H), 6.99 (d, J=8.4 Hz,1H), 4.35-4.29 (m, 4H), 3.91 (t, J=7.2 Hz, 3H), 3.19 (s, 3H), 2.61 (t,J=7.4 Hz, 2H), 2.24 (s, 3H). HRMS (ESI⁺): calcd for C₃₀H₂₉N₄O₆ (M+H)⁺,541.2082; found 541.2075.

Preparation of Compound 211, tert-butyl(4-((6-bromoquinolin-2-yl)oxy)butyl)carbamate

NaH (60%) (0.095 g, 2.378 mmol) was added to a solution of4-(Boc-amino)-1-butanol (0.432 mL, 2.378 mmol) in dry THF (7 mL) at 0°C. The reaction mixture was stirred for 5 min, then allowed to warm toroom temperature and stirred for 30 min. 6-Bromo-2-chloroquinoline(0.481 g, 1.981 mmol) was added and the reaction mixture was heated toreflux for 4.5 h. The reaction was allowed to cool, concentrated toremove THF and diluted with water (10 mL) and sat. NaHCO₃ aq. (10 mL).The aqueous layer was extracted with DCM (3×10 mL) and the organic phasedried (MgSO₄), filtered and concentrated. Purification by biotagechromatography using a gradient of 3 to 30% EtOAc/cyclohexane affordedthe title compound as an off-white solid (484 mg, 62%). ¹H NMR (500 MHz,Chloroform-d) δ 7.89 (d, J=8.9 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.71 (d,J=8.8 Hz, 1H), 7.68 (dd, J=8.9, 2.1 Hz, 1H), 6.91 (d, J=8.9 Hz, 1H),4.68 (br s, 1H), 4.48 (t, J=6.5 Hz, 2H), 3.24 (q, J=6.0 Hz, 2H),1.92-1.82 (m, 2H), 1.70 (p, J=7.3 Hz, 2H), 1.46 (s, 9H). HRMS (ESI⁺):calcd for C₁₈H₂₄ ⁷⁹BrN₂O₃(M+H)*, 395.0970; found 395.0695.

Preparation of Compound 212,2-(4-((tert-butoxycarbonyl)amino)butoxy)quinoline-6-carboxylic acid

n-BuLi (2.1 M in hexanes, 0.632 mL, 1.328 mmol) was added drop-wise to asolution of Compound 211 (250 mg, 0.632 mmol) in dry THF (7.5 mL) at−78° C. The reaction was stirred at −78° C. for 40 min before solid CO₂was added. After stirring for few min, the reaction mixture was allowedto warm nearly to room temperature. The reaction mixture was quenchedwith water (5 mL), then concentrated to remove THF, diluted with water(10 mL), washed with EtOAc (1×10 mL)—with brine was added to clear. Theaqueous phase was acidified with 2 M HCl aq. (˜to pH 2-3) then extractedwith DCM (2×10 mL) and EtOAc (2×10 mL). The combined organic phase wasdried (Na₂SO₄) and concentrated in vacuo to afford the title compound asa white solid (90 mg, 40%). ¹H NMR (500 MHz, DMSO-d6) δ 13.07 (br s,OH), 8.56 (d, J=1.9 Hz, 1H), 8.41 (d, J=8.8 Hz, 1H), 8.13 (dd, J=8.7,2.0 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.09 (d, J=8.9 Hz, 1H), 6.87 (t,J=5.6 Hz, 1H), 4.44 (t, J=6.6 Hz, 2H), 3.00 (q, J=6.7 Hz, 2H), 1.77 (p,J=6.6 Hz, 2H), 1.55 (p, J=7.2 Hz, 2H), 1.38 (s, 9H). HRMS (ESI⁺): calcdfor C₁₉H₂₅N₂O₅ (M+H)⁺, 361.1763; found 361.1767.

Example 164, tert-butyl(4-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)carbamoyl)quinolin-2-yl)oxy)butyl)carbamate

HATU (108 mg, 0.283 mmol) was added to a solution of Compound 212 (85mg, 0.236 mmol) and DIEA (0.123 mL, 0.708 mmol) in dry DMF (2.0 mL). Thereaction was allowed to stir for 3 min before Compound 2 (79 mg, 0.236mmol) was added and the reaction left to stir at room temperature for 19h. The reaction mixture was diluted with water (20 ml) and the aqueouslayer extracted with EtOAc (3×15 ml)—brine was added to clear. Thecombined organic layer was washed with brine (15 ml), dried (MgSO₄) andconcentrated in vacuo, remaining traces of DMF were removed byco-evaporation with heptane. Purification by biotage chromatographyusing a gradient of 5 to 40% EtOAc/DCM afforded a brown gum. The productalthough otherwise clean, still contained DMF therefore the sample wasre-dissolved in EtOAc (15 ml) and washed with water (1×15 ml) and brine(2×15 ml). The organic layer was dried (MgSO₄) and concentrated invacuo. Heptane was used in an attempt to remove any remaining DMF anddried under vacuum to afford the title compound as a brown tacky solid(60 mg, 41%). ¹H NMR (500 MHz, Methanol-d4) δ 8.48 (d, J=1.9 Hz, 1H),8.26 (d, J=8.9 Hz, 1H), 8.21 (dd, J=8.7, 2.0 Hz, 1H), 7.92 (d, J=8.7 Hz,1H), 7.80 (d, J=2.2 Hz, 1H), 7.55 (dd, J=8.3, 2.2 Hz, 1H), 7.50 (d,J=2.0 Hz, 1H), 7.49 (d, J=2.2 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.31 (d,J=8.4 Hz, 1H), 7.05 (d, J=8.9 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 4.54 (t,J=6.5 Hz, 2H), 4.34-4.29 (m, 4H), 3.37 (s, 3H), 3.17 (t, J=7.0 Hz, 2H),2.34 (s, 3H), 1.94-1.86 (m, 2H), 1.74-1.66 (m, 2H), 1.46 (s, 9H). HRMS(ESI⁺): calcd for C₃₅H₃₈N₄O₇ (M+H)⁺, 627.2813; found 627.2800.

Preparation of Compound 213,1-(4-bromo-2-nitrophenyl)-N,N-dimethylmethanamine

To a solution of 4-bromo-2-nitrobenzaldehyde (228 mg, 0.991 mmol) indichloromethane (10 mL) at room temperature was added dimethylamine (2.0M in THF, 0.743 mL, 1.487 mmol). The reaction was allowed to stir atroom temperature for 1.5 h before NaBH(OAc)₃ (315 mg, 1.487 mmol) wasadded. The reaction mixture was allowed to stir 16 h. Furtherdimethylamine (2.0 M in THF, 0.743 mL, 1.487 mmol) was added. Thereaction was allowed to stir at room temperature for 2.0 h beforeadditional NaBH(OAc)₃ (315 mg, 1.487 mmol) was added. The reaction wasallowed to stir overnight for 16 h, then diluted with DCM (10 mL),washed with NaHCO₃ (1×10 mL) and the aqueous phase extracted with DCM(1×10 mL). The combined organic phase was dried (MgSO₄) and concentratedto afford the crude material as a yellow oil. Purification by biotagechromatography (KP-NH2 column) using a gradient of 0 to 40%EtOAc/cyclohexane afforded the required product as a yellow oil (179 mg,70%). ¹H NMR (500 MHz, Chloroform-d) δ 8.03 (br s, 1H), 7.76-7.63 (m,2H), 3.78 (s, 2H), 2.32 (s, 6H). HRMS (ESI⁺): calcd for C₉H₂₇ ⁷⁹BrN₂O₂(M+H)⁺, 259.0077; found 259.0074.

Preparation of Compound 214, 5-bromo-2-((dimethylamino)methyl)aniline

A mixture of Compound 213 (101 mg, 0.390 mmol) and SnCl₂.2H₂O (440 mg,1.95 mmol) in EtOAc (3.0 mL) and DCM (1.0 mL) was stirred at rt for 24h, and then carefully poured into sat. aq NaHCO₃ (30 ml), then filteredto remove solids. The aqueous layer was then extracted with DCM (3×15ml). The combined organic layers were dried (Na₂SO₄) and concentrated invacuo to afford the crude product as a yellow oil. This material aspurified by SCX chromatography, eluting with MeOH then 10% 2M NH₃/MeOHto afford the title compound (55 mg, 62%). ¹H NMR (500 MHz, DMSO-d6) δ6.85 (d, J=7.9 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 6.61 (dd, J=7.9, 2.1 Hz,1H), 5.51 (br s, 2H), 3.24 (s, 2H), 2.10 (s, 6H). HRMS (ESI⁺): calcd forC₉H₁₃ ⁸¹BrN₂(M+H)⁺, 231.0315; found 231.0318.

Preparation of Compound 215,N-(5-bromo-2-((dimethylamino)methyl)phenyl)-2-methylquinoline-6-carboxamide

Oxalyl chloride (0.032 mL, 0.378 mmol) was added drop-wise to a solutionof 2-methyl-6-quinoline carboxylic acid (62.5 mg, 0.334 mmol) and DMF(0.431 μL, 5.56 μmol) in dry DCM (2 mL). The reaction mixture wasallowed to stir for 1.5 h. The solvent was removed in vacuo, a furtherportion of anhydrous DCM (2 ml) was added and then removed in vacuo. Theresulting residue was re-dissolved in DCM (1 ml×2) and added to asolution of Compound 214 (51 mg, 0.223 mmol) and pyridine (0.090 mL,1.113 mmol) in anhydrous DCM (2 ml). The reaction was left to stir for19 h, then poured into sat. aq. NaHCO₃ aq. (20 mL) and the aqueous layerextracted with DCM (3×15 ml). The combined organic layer was washed withbrine (15 ml), dried (Na₂SO₄) and concentrated in vacuo to afford thecrude product as a green oil. Purification by biotage chromatographywith a KP-NH column using a gradient of 0 to 100% EtOAc/cyclohexaneafforded the required product as a green solid (45 mg, 51%). ¹H NMR (500MHz, Chloroform-d) δ 12.10 (s, 1H), 8.78 (s, 1H), 8.42 (s, 1H),8.18-8.07 (m, 3H), 7.39 (d, J=8.4 Hz, 1H), 7.22-7.19 (m, 1H), 7.02 (d,J=8.0 Hz, 1H), 3.61 (s, 2H), 2.81 (s, 3H), 2.40 (s, 6H). HRMS (ESI⁺):calcd for C₂₀H₂₀ ⁷⁹BrN₃O (M+H)⁺, 398.0868; found 398.0858.

Preparation of Compound 216,N-(2-((dimethylamino)methyl)-5-((diphenylmethylene)amino)phenyl)-2-methylquinoline-6-carboxamide

Palladium acetate (2.42 mg, 0.011 mmol) was added to a suspension ofCompound 215 (43 mg, 0.108 mmol), xantphos (12.49 mg, 0.022 mmol),cesium carbonate (70.4 mg, 0.216 mmol) and benzophenone imine (21.5 mg,0.119 mmol) in anhydrous dioxane (1.2 ml). The reaction was degassed by4× vacuum/argon cycles and heated to 100° C. for 22 h. Furtherpalladium(II) acetate (2.424 mg, 10.80 μmol) and xantphos (12.49 mg,0.022 mmol) were added and the reaction allowed to heat at 100° C. for24 h. The reaction was diluted with DCM (30 ml) and the solids werefiltered off. The filtrate was washed with water (10 ml), brine (10 ml),dried Na₂SO₄ and concentrated in vacuo. Purification by biotagechromatography (KP-NH2 column) using a gradient of 8 to 100%EtOAc/cyclohexane gave the title compound as a pale yellow solid (16.5mg, 31%). HRMS (ESI⁺): calcd for C₃₃H₃₁N₄₀ (M+H)⁺, 499.2498; found499.2492.

Example 165,N-(5-amino-2-((dimethylamino)methyl)phenyl)-2-methylquinoline-6-carboxamide

To a stirring solution of Compound 216 (17 mg, 0.034 mmol) in THF (0.5mL) at room temperature was slowly added 2M HCl aq. (0.043 mL, 0.085mmol). The reaction was allowed to stir at room temperature for 2.25 h.The solvents were removed in vacuo and traces of water removed byco-evaporation with toluene. The resulting residue was then taken up inDCM/MeOH and dried (Na₂SO₄), filtered and concentrated again to affordN-(5-amino-2-((dimethylamino)methyl)phenyl)-2-methylquinoline-6-carboxamide.Oxalyl chloride (4.73 μL, 0.056 mmol) was added drop-wise to a solutionof 1,4-benzodioxane carboxylic acid (8.89 mg, 0.049 mmol) and DMF (0.064μL, 0.822 μmol) in dry DCM (0.5 mL). The RM was allowed to stir for 1.5h at room temperature. Further DMF (0.064 μL, 0.822 μmol) and oxalylchloride (4.73 μL, 0.056 mmol) were added and the reaction stirred for1.5 h. The DCM was then removed in vacuo. A further portion of anhydrousDCM (2 ml) was added and removed in vacuo. The resulting residue wasre-dissolved in DCM (1 ml×2) and added to a solution ofN-(5-amino-2-((dimethylamino)methyl)phenyl)-2-methylquinoline-6-carboxamide(11 mg, 0.033 mmol) and pyridine (0.027 mL, 0.329 mmol) in anhydrous DCM(0.5 ml). Dioxane (0.5 mL) and DMF (0.5 mL) were added in an attempt tosolubilise all solids in the reaction. The reaction was left to stir for17 h. Further acid chloride was prepared [to form 5 equivalents, usingthe same procedure as previously and oxalyl chloride (14.0 μL, 0.165mmol), benzodioxane carboxylic acid (29.7 mg, 0.165 mmol) and DMF (0.32μL, 4.11 μmol)]. The reaction was allowed to stir at room temperaturefor 22 h. The reaction was partitioned between DCM (10 mL) and 1M NaOH(10 ml). The aqueous layer was extracted with a further portion of DCM(10 mL) and the combined organic layer washed with brine (10 ml) anddried (Na₂SO₄). Then concentrated in vacuo to afford the crude productas a yellow oil (16 mg). Purification by column chromatography using agradient of 0 to 6% MeOH/DCM afforded the title compound as a whitesolid (8.8 mg, 54%). ¹H NMR (500 MHz, DMSO-d6) δ 12.08 (s, 1H), 10.18(s, 1H), 8.74 (d, J=1.9 Hz, 1H), 8.45 (d, J=1.9 Hz, 1H), 8.44 (d, J=8.5Hz, 1H), 8.17 (dd, J=8.8, 2.0 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.60 (dd,J=8.2, 2.1 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.54 (dd, J=8.4, 3.0 Hz,3H), 7.20 (d, J=8.3 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 4.34-4.29 (m, 4H),3.66 (s, 2H), 2.71 (s, 3H), 2.34 (s, 6H). HRMS (ESI⁺): calcd forC₂₉H₂₉N₄O₄ (M+H)⁺, 497.2183; found 497.2171.

Preparation of Compound 217, (4-bromo-2-nitrophenyl)methanol

To a stirring suspension of 4-bromo-2-nitrobenzaldehyde (550 mg, 2.391mmol) in ethanol (14 mL) and water (7 mL) at 0° C. was added sodiumborohydride (452 mg, 11.96 mmol) and the reaction left to stir at 0° C.for 17.5 h. The reaction was diluted with water (30 ml), and extractedwith EtOAc (2×30 ml)—brine was added to clear. The combined organiclayer was washed with brine (30 ml), dried (MgSO₄) and concentrated invacuo to afford the title compound as a yellow solid (536 mg, 97%). ¹HNMR (500 MHz, Chloroform-d) δ 8.27 (d, J=2.0 Hz, 1H), 7.82 (dd, J=8.3,2.0 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 4.98 (s, 2H).

Preparation of Compound 218, 4-bromo-1-(methoxymethyl)-2-nitrobenzene

To a stirring solution of Compound 217 (313 mg, 1.349 mmol) in DCM (4.0mL) was added a solution of sodium hydroxide (405 mg, 10.12 mmol) inwater (4.0 mL). The reaction was allowed to stir for 10 min beforetetrabutylammonium hydrogen sulfate (458 mg, 1.349 mmol) was added,followed by dimethyl sulfate (0.256 mL, 2.70 mmol). The reaction wasleft to stir at room temperature for 20 h, then diluted with DCM (20 ml)and washed with water (20 ml), brine (20 ml), dried (Na₂SO₄) andconcentrated in vacuo to give the crude product as a yellow/brown oil.Purification by column chromatography using a gradient of 5 to 40%EtOAc/cyclohexane gave the title compound as a pale yellow solid (289mg, 87%). ¹H NMR (500 MHz, Chloroform-d) δ 8.24 (d, J=2.0 Hz, 1H), 7.79(dd, J=8.4, 2.0 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 4.80 (s, 2H), 3.51 (s,3H).

Preparation of Compound 219, 5-bromo-2-(methoxymethyl)aniline

SnCl₂.2H₂O (702 mg, 3.11 mmol) was added to a stirring solution ofCompound 218 (153 mg, 0.622 mmol) in ethyl acetate (4.5 mL) and DCM (1.5mL). The reaction was allowed to stir at room temperature for 20 h. Thereaction was carefully poured into sat. NaHCO₃ aq. (30 ml), thenfiltered. The aqueous layer was extracted with DCM (3×15 ml) and thecombined organic layer dried (Na₂SO₄) and concentrated in vacuo toafford the title compound as a yellow oil (95 mg, 71%). ¹H NMR (500 MHz,Chloroform-d) δ 6.93 (d, J=7.9 Hz, 1H), 6.89 (d, J=1.8 Hz, 1H), 6.86(dd, J=7.9, 1.9 Hz, 1H), 4.44 (s, 2H), 3.34 (s, 3H).

Preparation of Compound 220,N-(5-bromo-2-(methoxymethyl)phenyl)-2-methylquinoline-6-carboxamide

Oxalyl chloride (0.060 mL, 0.708 mmol) was added drop-wise to a solutionof 2-methyl-6-quinoline carboxylic acid (117 mg, 0.625 mmol) and DMF(0.806 μL, 10.41 μmol) in anhydrous DCM (4 mL). The reaction was allowedto stir for 1 h. The solvent was removed in vacuo. Two further portionsof anhydrous DCM (2 ml) were added and removed in vacuo. The resultingresidue was re-dissolved in DCM (1 ml×2) and added to a solution ofCompound 219 (90 mg, 0.417 mmol) and pyridine (0.168 mL, 2.083 mmol) inanhydrous DCM (2 ml). The reaction mixture was allowed to stir for 2 hat room temperature, then poured into sat. NaHCO₃ aq. and the aqueouslayer extracted with DCM (3×15 ml). The combined organic layer waswashed with brine (15 ml), dried (Na₂SO₄) and concentrated in vacuo toafford the crude product as a green semi-solid which was dry-loaded onto silica. Purification by biotage chromatography using a gradient of 6to 50% EtOAc/cyclohexane gave the title compound as an off-white solid(83 mg, 52%). ¹H NMR (500 MHz, Chloroform-d) δ 9.86 (s, 1H), 8.73 (d,J=1.9 Hz, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.17 (d,J=8.8 Hz, 1H), 8.13 (dd, J=8.8, 2.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H),7.26 (dd, J=8.1, 2.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 4.65 (s, 2H), 3.50(s, 3H), 2.83 (s, 3H). HRMS (ESI⁺): calcd for C₁₉H₁₈ ⁷⁹BrN₂O₂ (M+H)⁺,385.0552; found 385.0541.

Preparation of Compound 221,N-(5-((diphenylmethylene)amino)-2-(methoxymethyl)phenyl)-2-methylquinoline-6-carboxamide

Palladium acetate (4.72 mg, 0.210 mmol) was added to a suspension ofCompound 220 (81 mg, 0.210 mmol), xantphos (24.33 mg, 0.231 mmol),cesium carbonate (137 mg, 0.421 mmol) and benzophenone imine (0.039 mL,0.231 mmol) in anhydrous dioxane (2.0 ml). The reaction was degassed by4× vacuum/argon cycles and heated to 100° C. for 23 h. Furtherpalladium(II) acetate (4.72 mg, 0.210 mmol) and xantphos (24.33 mg,0.231 mmol) were added and the reaction allowed to heat at 100° C. for 3days. The reaction was diluted with DCM (30 ml) and filtered. Thefiltrate was washed with water (10 ml), brine (10 ml), dried (Na₂SO₄)and concentrated in vacuo. Purification by biotage chromatography usinga gradient of 12 to 100% EtOAc/cyclohexane gave the title compound as ayellow solid (54 mg, 53%). HRMS (ESI⁺): calcd for C₃₂H₂₈N₃O₂ (M+H)⁺,486.2182; found: 486.2192.

Example 166,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(methoxymethyl)phenyl)-2-methylquinoline-6-carboxamide

To a stirring solution of Compound 221 (49 mg, 0.101 mmol) in THF (1.0mL) at room temperature was slowly added 2M HCl aq. (0.126 mL, 0.252mmol). The reaction was allowed to stir at room temperature for 3 h. Thesolvents were removed in vacuo and the remaining traces of water wereremoved by co-evaporation with toluene. The crudeN-(5-amino-2-(methoxymethyl)phenyl)-2-methylquinoline-6-carboxamide wasfurther dried under high vacuum.

Oxalyl chloride (0.015 mL, 0.171 mmol) was added dropwise to a solutionof 1,4-benzodioxane carboxylic acid (27.2 mg, 0.151 mmol) andN,N-dimethylformamide (0.195 μL, 2.52 μmol) in anhydrous DCM (1.0 mL).The reaction was allowed to stir for 1.5 h. The solvent was removed invacuo, a further portion of anhydrous DCM (2 ml) was added andconcentrated again.

The resulting residue was re-dissolved in DCM (1 ml+0.5 ml) and added toa solution ofN-(5-amino-2-(methoxymethyl)phenyl)-2-methylquinoline-6-carboxamide(32.4 mg, 0.101 mmol) and pyridine (0.082 mL, 1.008 mmol) in anhydrousDCM (2.0 ml) and anhydrous DMF (0.5 ml). The reaction was left to stirfor 21 h, then diluted with DCM (10 ml) and washed with sat. NH₄Cl aq.(10 ml), water (2×10 ml), brine (10 ml) and dried (Na₂SO₄) to afford thecrude product as a yellow oil. An attempt to purify the material bycolumn chromatography using a gradient of 5 to 75% EtOAc/DCM failed toprovide pure product. Therefore this material was further purified bypreparative TLC (3:1 DCM/EtOAc) to afford the title compound as a whitesolid (2 mg, 4%). ¹H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 10.17 (s,1H), 8.58 (br s, 1H), 8.43 (d, J=8.4 Hz, 1H), 8.23-8.20 (m, 1H),8.15-8.13 (m, 1H), 8.06 (d, J=8.7 Hz, 1H), 7.71-7.68 (m, 1H), 7.58-7.52(m, 3H), 7.39 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 4.52 (s, 2H),4.35-4.29 (m, 4H), 3.33 (s, 3H), 2.72 (s, 3H). HRMS (ESI⁺): calcd forC₂₈H₂₆N₃O₅ (M+H)⁺, 484.1872; found: 484.1848.

Example 167,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(hydroxymethyl)phenyl)-2-methylquinoline-6-carboxamide

Following the same procedure as for Example 166, a side product wasisolated by preparative TLC (1:1 EtOAc/DCM) to afford the title compoundas a white solid (1.2 mg, 2.5%). ¹H NMR (500 MHz, MeOD/CDCl₃, 6:1) δ8.55 (d, J=2.0 Hz, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.29-8.25 (m, 2H), 8.09(d, J=8.8 Hz, 1H), 7.61 (dd, J=8.2, 2.2 Hz), 7.54 (d, J=8.5 Hz, 1H),7.51 (d, J=2.1 Hz, 1H), 7.49 (dd, J=8.3, 2.2 Hz), 7.39 (d, J=8.3 Hz,1H), 6.95 (d, J=8.4 Hz, 1H), 4.77 (s, 2H), 4.34-4.29 (m, 4H), 2.79 (s,3H). HRMS (ESI⁺): calcd for C₂₇H₂₄N₃O₅ (M+H)⁺, 470.1710; found:470.1690.

Preparation of Compound 222,5-bromo-1-methyl-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide

Iodomethane (0.045 mL, 0.726 mmol) was added to a stirring suspension of5-bromo-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide (150 mg, 0.605 mmol)and potassium carbonate (125 mg, 0.907 mmol) in anhydrous DMF (6 mL) atroom temperature under argon. The reaction was allowed to stir for 17.5h. The reaction mixture was poured into brine (20 ml) and the aqueouslayer extracted with DCM (2×20 ml). The combined organic layer waswashed with brine (20 ml), dried (Na₂SO₄) and concentrated in vacuo,high vacuum was used to remove remaining traces of DMF. Purification bybiotage chromatography using a gradient of 5 to 40% EtOAc/cyclohexanegave the title compound as an off-white solid (130 mg, 82%). ¹H NMR (500MHz, Chloroform-d) δ 7.49-7.45 (m, 1H), 7.41-7.39 (m, 1H), 6.63 (d,J=8.5 Hz, 1H), 4.34 (s, 2H), 3.14 (s, 3H).

Preparation of Compound 223, 2-(trimethylsilyl)ethyl1-methyl-1,3-dihydrobenzo[c]isothiazole-5-carboxylate 2,2-dioxide

To a stirring suspension of Compound 222 (116 mg, 0.443 mmol), Hermann'spalladacycle (20.8 mg, 0.022 mmol) and tri-t-butylphosphoniumtetrafluoroborate (25.7 mg, 0.089 mmol) in 2-(trimethylsilyl)-ethanol(3.5 mL) was added molybdenum hexacarbonyl (234 mg, 0.885 mmol) followedby DBU (0.20 ml, 1.328 mmol). The reaction mixture was heated to 130° C.in a microwave for 1 h. The reaction mixture was filtered to removesolids and the filtrate concentrated under high vacuum to remove thesolvent. The resulting residue was taken up in DCM (20 ml) and washedwith sat. NH₄Cl aq. (25 ml), water (25 ml—brine had to be added toclear) and brine (5 ml), dried (Na₂SO₄) and concentrated in vacuo toafford the crude product as a brown oil. Purification by biotagechromatography using a gradient of 5 to 40% EtOAc/cyclohexane gave thetitle compound as a pale yellow oil (25 mg, 17%). ¹H NMR (500 MHz,Chloroform-d) δ 8.09-8.05 (m, 1H), 7.96-7.94 (m, 1H), 6.76 (d, J=8.4 Hz,1H), 4.44-4.40 (m, 2H), 4.40 (s, 2H), 3.21 (s, 3H), 1.19-1.02 (m, 2H),0.10 (s, 9H). HRMS (ESI⁺): calcd for C₁₂H₁₇NO₄SSi (M−2×Me)+, 300.0720;found: 300.0722.

Example 168,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-1-methyl-1,3-dihydrobenzo[c]isothiazole-5-carboxamide2,2-dioxide

To a stirring solution of Compound 223 (24 mg, 0.073 mmol) in THF (1.0mL) at room temperature under argon was slowly added TBAF (1.0M in THF,0.110 mL, 0.110 mmol) the reaction mixture was allowed to stir for 3 h.Water (10 ml) was added and the reaction mixture concentrated to removeTHE. The aqueous layer was acidified (to ˜pH 3) using 1M HCl aq. andextracted with EtOAc (3×15 ml)—brine was added to clear. The combinedorganic layer was washed with brine (10 ml), dried (Na₂SO₄) andconcentrated in vacuo to afford1-methyl-1,3-dihydrobenzo[c]isothiazole-5-carboxylic acid 2,2-dioxide asa white semi-solid (31 mg). HATU (29.4 mg, 0.077 mmol) was added to astirring solution of1-methyl-1,3-dihydrobenzo[c]isothiazole-5-carboxylic acid 2,2-dioxide(17 mg, 0.064 mmol) and DIEA (0.034 mL, 0.193 mmol) in DMF (1 mL) atroom temperature under argon. The reaction was allowed to stir for 3 minbefore the addition of Compound 2 (18.29 mg, 0.064 mmol). The reactionwas left to stir at room temperature for 18 h, then diluted with water(10 ml) and extracted with EtOAc (3×15 ml). The combined organic layerwas washed with brine (15 ml), dried (Na₂SO₄) and concentrated in vacuo.Purification by column chromatography using a gradient of 0 to 10%EtOAc/DCM gave the title compound as a white solid (18 mg, 57%). ¹H NMR(500 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.86 (s, 1H), 8.05 (dd, J=8.3, 1.7Hz, 2H), 7.98 (br s, 1H), 7.80 (d, J=2.1 Hz, 1H), 7.57 (dd, J=8.3, 2.2Hz, 1H), 7.53 (d, J=2.1 Hz, 1H), 7.50 (dd, J=8.4, 2.2 Hz, 1H), 7.21 (d,J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.79 (s,2H), 4.34-4.28 (m, 4H)), 3.13 (s, 3H), 2.18 (s, 3H). HRMS (ESI⁺): calcdfor C_(2s)H₂₄N₃O₆S (M+H)⁺, 494.1386; found: 494.1364.

Compound 224, N-(2-fluoro-5-nitrophenyl)-2-methylquinoline-6-carboxamide

Oxalyl chloride (3.25 mL, 38.4 mmol) was added dropwise to a solution of2-methylquinoline-6-carboxylic acid (6.59 g, 35.2 mmol) and DMF (0.0062mL, 0.080 mmol) in dry DCM (80 mL). The reaction mixture was stirred atroom temperature for 3 h, and then concentrated. The residue wasdissolved in DCM and concentrated again. This residue was dissolved inpyridine (80 mL) and 2-fluoro-5-nitroaniline (5.00 g, 32.00 mmol) wasadded in one portion. The reaction mixture was stirred at roomtemperature for 18 h, and then poured onto water (100 mL). The greenprecipitate was filtered and washed several times with water, Et₂O andfinally with a minimum amount of DCM to afford the title compound (10.42g, 100%) as a light green solid which does not require furtherpurification. ¹H NMR (500 MHz, DMSO) δ 10.70 (s, 1H), 8.72 (dd, J=6.45,2.93 Hz, 1H), 8.63 (d, J=2.02 Hz, 1H), 8.43 (d, J=8.46 Hz, 1H), 8.23(dd, J=8.48, 2.02 Hz, 1H), 8.21-8.16 (m, 1H), 8.05 (d, J=8.86 Hz, 1H),7.65 (app t, J=9.25 Hz, 1H), 7.54 (d, J=8.46 Hz, 1H), 2.71 (s, 3H). HRMS(ESI⁺): Found [M+H]+ 326.0934 C₁₇H₁₃FN₃O₃ requires 326.0935.

Compound 225, N-(5-amino-2-fluorophenyl)-2-methylquinoline-6-carboxamide

To a solution ofN-(2-fluoro-5-nitrophenyl)-2-methylquinoline-6-carboxamide (10.42 g,32.00 mmol) in ethanol (120 mL) and water (40 mL), ammonium chloride(11.99 g, 224 mmol) and iron powder (12.52 g, 224 mmol) were added andthe resulting suspension was allowed to stir at 90° C. for 1 hour. Thereaction mixture was allowed to cool to room temperature, diluted withMeOH and DCM and filtered through a pad of Celite. The resultingfiltrate was concentrated under vacuum to afford a light brown solid ascrude product, which was taken directly onto the next step without anyfurther purification (9.46 g, 100%). ¹H-NMR (500 MHz, DMSO) δ 10.05 (s,1H), 8.57 (d, J=1.67 Hz, 1H), 8.39 (d, J=8.74 Hz, 1H), 8.19 (dd, J=8.74,1.67 Hz, 1H), 8.01 (d, J=8.74 Hz, 1H), 7.52 (d, J=8.33 Hz, 1H), 6.94(dd, J=9.78, 8.28 Hz, 1H), 6.89 (dd, J=6.58, 2.74 Hz, 1H), 6.46-6.39 (m,1H), 5.05 (bs, 2H), 2.70 (s, 3H). HRMS (ESI⁺): Found [M+H]⁺ 296.1191C₁₇H₁₅FN₃O requires 296.1194.

Compound 226,N-(4-fluoro-3-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

4-fluoro-3-nitroaniline (1.00 g, 6.41 mmol),2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (1.154 g, 6.41 mmol)and EDC (3.07 g, 16.01 mmol) were dissolved in dry DMF (45 mL), thenpyridine was added dropwise and the resulting orange/brown mixture wasallowed to stir at room temperature for 72 hours. The reaction mixturewas then washed with water (2×50 mL) and extracted with a mixture ofDCM/MeOH 9:1 (2×50 mL). The organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure to afford an orange solid as crudeproduct, which was purified via flash column chromatography on silicagel in gradient (from 0 to 10% MeOH in DCM) to afford the title compoundas a pale yellow solid (0.98 g, 48%). ¹H-NMR (500 MHz, DMSO): δ 10.47(s, 1H), 8.69 (dd, J 6.48, 2.88 Hz, 1H), 8.13 (m, 1H), 7.58 (dd,J=11.12, 9.22 Hz, 1H), 7.55 (d, J=2.42 Hz, 1H), 7.52 (dd, J=8.08, 2.42Hz, 1H), 7.02 (d, J=8.08 Hz, 1H), 4.36-4.29 (m, 4H). HRMS (ESI⁺): Found[M+H]⁺ 319.0729 C₁₅H₁₂FN₂O₅ requires 319.0725.

Compound 227,N-(3-amino-4-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

To a solution ofN-(4-fluoro-3-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide(10.19 g, 32.00 mmol) in ethanol (100 mL) and water (33 mL), ammoniumchloride (11.99 g, 224 mmol) and iron powder (12.52 g, 224 mmol) wereadded and the resulting suspension was allowed to stir at 90° C. for 1hour. The reaction mixture was allowed to cool to room temperature,diluted with MeOH and DCM and filtered through a pad of Celite. Theresulting filtrate was concentrated under vacuum to afford a light brownsolid as crude product, which was taken directly onto the next stepwithout any further purification (9.23 g, 100%). ¹H-NMR (500 MHz, DMSO):δ 9.81 (s, 1H), 7.52-7.48 (m, 1H), 7.46 (dd, J=8.51, 1.76 Hz, 1H), 7.28(dd, J=8.51, 2.27 Hz, 1H), 6.96 (d, J=8.35 Hz, 1H), 6.91 (dd, J=10.60,9.10 Hz, 1H), 6.86-6.79 (m, 1H), 5.14 (bs, 2H), 4.33-4.26 (m, 4H). HRMS(ESI⁺): Found [M+H]⁺ 289.0990 C₁₅H₁₄FN₂O₃ requires 289.0983.

Compound 228,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-methylquinoline-6-carboxamide

Procedure A:N-(3-amino-4-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide(0.600 g, 2.081 mmol), 2-methylquinoline-6-carboxylic acid (0.468 g,2.498 mmol) and EDC (0.998 g, 5.20 mmol) were dissolved in dry DMF (12mL), then pyridine (0.84 mL, 10.41 mmol) was added dropwise and theresulting mixture was allowed to stir at room temperature for 48 hours.The reaction mixture was poured onto water (20 mL) and the precipitatewas washed several times with water and Et₂O to afford the crude productas a pale green solid, which was purified via flash columnchromatography on silica gel in gradient (from 0 to 10% MeOH in DCM) toafford the title compound as a pale yellow solid (0.45 g, 47%).

Procedure B: To a suspension of2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (12.70 g, 70.5 mmol)in dry DCM (100 mL), DMF (6.16 μl, 0.080 mmol) and oxalyl chloride (6.51mL, 77 mmol) were added dropwise and the resulting green solution wasallowed to stir at 20° C. for 3 hours after which it was concentratedunder vacuum to afford a dry pale green solid. The solid was dissolvedin pyridine (100 mL) andN-(5-amino-2-fluorophenyl)-2-methylquinoline-6-carboxamide (9.46 g, 32.0mmol) was added in one portion. The resulting dark yellow suspension wasallowed to stir for 2 hours after which it was poured onto water (100mL). The yellow precipitate was filtered and washed several times withwater, Et₂O and finally with a minimum amount of DCM to afford the crudeproduct as a pale yellow solid which does not require furtherpurification (12.5 g, 85%).

¹H-NMR (500 MHz, DMSO): δ 10.37 (s, 1H), 10.18 (s, 1H), 8.62 (d, J=1.65Hz, 1H), 8.41 (d, J=8.77 Hz, 1H), 8.23 (dd, J=8.77, 2.19 Hz, 1H), 8.13(dd, J=7.01, 2.63 Hz, 1H), 8.03 (d, J=8.51 Hz, 1H), 7.68-7.63 (m, 1H),7.55-7.53 (m, 2H), 7.52 (dd, J=8.51, 2.09 Hz, 1H), 7.29 (dd, J=9.98,8.69 Hz, 1H), 6.99 (d, J=8.51 Hz, 1H), 4.34-4.28 (m, 4H), 2.71 (s, 3H).HRMS (ESI⁺): Found [M+H]⁺ 458.1499 C₂₆H₂₁FN₃O₄ requires 458.1511.

Compound 229,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-formylquinoline-6-carboxamide

A solution ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-methylquinoline-6-carboxamide(5.00 g, 10.93 mmol) and selenium dioxide (1.334 g, 12.02 mmol) in dryDMF (40.00 mL) and dioxane (120.00 mL) was heated at 152° C. for 1 hafter which the reaction mixture was allowed to cool to roomtemperature, diluted with DCM and filtered through a pad of Celite. Thefiltrate was concentrated under vacuum to afford the crude product as ayellow solid which was taken directly onto the next step without anyfurther purification (5.15 g, 100%). ¹H-NMR (500 MHz, DMSO): 510.54 (s,1H), 10.19 (s, 1H), 10.17 (s, 1H), 8.81-8.77 (m, 1H), 8.39 (dd, J=8.73,1.95 Hz, 1H), 8.36 (d, J=8.73 Hz, 1H), 8.17 (dd, J=6.93, 2.57 Hz, 1H),8.09 (d, J=9.26 Hz, 1H), 7.69-7.64 (m, 1H), 7.55 (d, J=1.99 Hz, 1H),7.52 (dd, J=8.30, 1.99 Hz, 1H), 7.31 (app t, J=9.97 Hz, 1H), 6.99 (d,J=8.30 Hz, 1H), 4.36-4.27 (m, 4H). HRMS (ESI⁺): Found [M+H]⁺ 472.1290C₂₆H₁₉FN₃O₅ requires 472.1303.

Example 169,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide

A solution ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-formylquinoline-6-carboxamide(1.19 g, 2.52 mmol) and 1-ethylpiperazine in dry DCM (20 mL) was allowedto stir at 20° C. for 6 h, after which sodium triacetoxyborohydride(1.605 g, 7.57 mmol) was added in one portion and the resulting mixturewas allowed to stir at 20° C. for 2 h. The reaction was quenched withNaHCO₃ saturated aqueous solution (20 mL) and extracted with a mixtureDCM/MeOH 9/1 (3×20 mL). Purification via flash column chromatography onsilica gel in gradient DCM/MeOH from 0 to 20%, followed by wash in waterand trituration in Et₂O afforded the desired product as a white solid(0.950 g, 66%). ¹H-NMR (500 MHz, DMSO): δ 10.41 (s, 1H), 10.20 (s, 1H),8.66 (d, J=1.86 Hz, 1H), 8.49 (d, J=8.67 Hz, 1H), 8.26 (dd, J=8.67, 1.86Hz, 1H), 8.14 (dd, J=7.14, 2.55 Hz, 1H), 8.08 (d, J=8.67 Hz, 1H), 7.73(d, J=8.27 Hz, 1H), 7.69-7.62 (m, 1H), 7.55 (d, J=1.83 Hz, 1H), 7.53(dd, J=8.53, 1.83 Hz, 1H), 7.29 (app t, J=9.16 Hz, 1H), 6.99 (d, J=8.53Hz, 1H), 4.36-4.25 (m, 4H), 3.79 (s, 2H), 2.64-2.18 (m, 10H), 0.99 (t,J=6.41 Hz, 3H). HRMS (ESI⁺): Found [M+H]⁺ 570.2532 C₃₂H₃₃FN₅O₄ requires570.2511.

The following compounds were synthesised according to the procedure forExample 169, by substituting the appropriate amine for1-ethylpiperazine.

-   Example 170,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(pyrrolidin-1-ylmethyl)quinoline-6-carboxamide-   Example 171,    2-(azetidin-1-ylmethyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)quinoline-6-carboxamide-   Example 172,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(piperidin-1-ylmethyl)quinoline-6-carboxamide-   Example 173,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide-   Example 174,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(piperazin-1-ylmethyl)quinoline-6-carboxamide-   Example 175,    (S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((2-methylpyrrolidin-1-yl)methyl)quinoline-6-carboxamide-   Example 176,    (R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((2-methylpyrrolidin-1-yl)methyl)quinoline-6-carboxamide-   Example 177,    2-((4-(tert-butyl)piperazin-1-yl)methyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)quinoline-6-carboxamide-   Example 178,    2-((4-cyclopropylpiperazin-1-yl)methyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)quinoline-6-carboxamide-   Example 179,    2-((4-(sec-butyl)piperazin-1-yl)methyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)quinoline-6-carboxamide-   Example 180,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)quinoline-6-carboxamide-   Example 181,    2-(2-azaspiro[3.3]heptan-2-ylmethyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)quinoline-6-carboxamide-   Example 182,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((3-methylazetidin-1-yl)methyl)quinoline-6-carboxamide-   Example 183,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((3,3-dimethylazetidin-1-yl)methyl)quinoline-6-carboxamide-   Example 184,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethyl-1,4-diazepan-1-yl)methyl)quinoline-6-carboxamide

TABLE E Compound 1H NMR Mass Spec Example ¹H-NMR (500 MHz, DMSO): δ10.39 (s, 1H), 10.18 (s, 1H), Found [M + H]⁺ 170 8.64 (d, J = 1.77 Hz,1H), 8.48 (d, J = 8.39 Hz, 1H), 8.24 527.2074 (dd, J = 8.39, 1.77 Hz,1H), 8.14 (dd, J 2.82 Hz, 7.33 Hz, C₃₀H₂₈FN₄O₄ 1H), 8.08 (1H, d, J 8.51Hz, CH), 7.72 (d, J = 8.51 Hz, 1H), requires 7.68-7.63 (m, 1H), 7.54 (d,J 2.13 Hz, 1H), 7.52 (dd, J = 527.2089 8.52, 2.13 Hz, 1H), 7.29 (app t,J = 9.39 Hz, 1H), 6.99 (d, J = 8.52 Hz, 1H), 4.34-4.27 (m, 4H), 3.92 (s,2H), 2.63- 2.50 (m, 4H), 1.80-1.69 (m, 4H). Example ¹H-NMR (500 MHz,MeOD): δ 8.59 (d, J = 1.90 Hz, 1H), Found [M + H]⁺ 171 8.48 (d, J = 8.87Hz, 1H), 8.29 (dd, J = 8.87, 1.90 Hz, 1H), 513.1930 8.19 (dd, J = 6.97,3.17 Hz, 1H), 8.15 (d, J = 8.87 Hz, 1H), C₂₉H₂₆FN₄O₄ 7.66 (d, J = 8.87Hz, 1H), 7.62-7.58 (m, 1H), 7.51 (d, J = requires 2.28 Hz, 1H), 7.49(dd, J = 8.38, 2.28 Hz, 1H), 7.24 (dd, J = 513.1933 9.90, 8.76 Hz, 1H),6.96 (d, J = 8.38 Hz, 1H), 4.36-4.29 (m, 4H), 3.99 (s, 2H), 3.47 (t, J =7.30 Hz, 4H), 2.21 (qn, J = 7.30 Hz, 2H). Example ¹H-NMR (500 MHz,DMSO): δ 10.39 (s, 1H), 10.18 (s, 1H), Found [M + H]⁺ 172 8.64 (s, 1H),8.48 (d, J = 8.55 Hz, 1H), 8.24 (d, J = 8.55 541.2242 Hz, 1H), 8.14 (dd,J = 7.08, 2.26 Hz, 1H), 8.08 (d, J = 8.55 C₃₁H₃₀FN₄O₄ Hz, 1 H), 7.74(app d, J = 7.60 Hz, 1H), 7.68-7.63 (m, 1H), requires 7.54 (s, 1H), 7.52(d, J = 8.55 Hz, 1H), 7.29 (app t, J = 8.93 541.2246 Hz, 1H), 6.99 (d, J= 7.60 Hz, 1H), 4.37-4.28 (m, 4H), 3.75 (s, 2H), 2.48-2.37 (m, 4H),1.63-1.48 (m, 4H), 1.47-1.36 (m, 2H). Example ¹H-NMR (500 MHz, DMSO): δ10.40 (s, 1H), 10.19 (s, 1H), Found [M + H]⁺ 173 8.65 (d, J = 1.68 Hz,1H), 8.49 (d, J = 8.40 Hz, 1H), 8.25 556.2329 (dd, J = 8.40, 1.68 Hz,1H), 8.14 (dd, J = 7.56, 2.52 Hz, C₃₁H₃₁FN₅O₄ 1H), 8.08 (d, J = 8.81 Hz,1H), 7.72 (d, J = 8.40 Hz, 1H), requires 7.68-7.63 (m, 1H), 7.55 (d, J =2.52 Hz, 1H), 7.52 (dd, J = 556.2355 8.40, 1.68 Hz, 1H), 7.29 (app t, J= 9.24 Hz, 1H), 6.99 (d, J = 9.24 Hz, 1H), 4.37-4.27 (m, 4H), 3.79 (s,2H), 2.54-2.27 (m, 8H), 2.16 (m, 3H). Example ¹H-NMR (500 MHz, DMSO): δ10.41 (s, 1H), 10.20 (s, 1H), Found [M + H]⁺ 174 8.73 (bs, 1H), 8.67 (d,J = 1.66 Hz, 1H), 8.52 (d, J = 8.71 542.2190 Hz, 1H), 8.27 (dd, J =8.71, 1.66 Hz, 1H), 8.15 (dd, J = C₃₀H₂₉FN₅O₄ 7.08, 2.72 Hz, 1H), 8.09(d, J = 8.71 Hz, 1H), 7.74 (d, J = requires 8.42 Hz, 1H), 7.66-7.61 (m,1H), 7.54 (d, J = 2.11 Hz, 1H), 542.2198 7.52 (dd, J = 8.42, 2.11 Hz,1H), 7.30 (app t, J = 10.10 Hz, 1H), 6.99 (d, J = 8.42 Hz, 1H),4.35-4.27 (m, 4H), 3.89 (s, 2H), 3.19-3.09 (m, 4H), 2.76-2.66 (m, 4H).Example ¹H-NMR (500 MHz, DMSO): δ 10.38 (s, 1H), 10.18 (s, 1H), Found[M + H]⁺ 175 8.64 (d, J = 1.79 Hz, 1H), 8.47 (d, J = 8.51 Hz, 1H), 8.24541.2237 (dd, J = 8.51, 1.79 Hz, 1H), 8.14 (dd, J = 7.17, 2.69 Hz,C₃₁H₃₀FN₄O₄ 1H), 8.08 (d, J = 8.51 Hz, 1H), 7.71 (d, J = 8.28 Hz, 1H),requires 7.68-7.63 (m, 1H), 7.54 (d, J = 2.07 Hz, 1H), 7.52 (dd, J =541.2246 8.28, 2.07 Hz, 1H), 7.29 (app t, J = 10.01 Hz, 1H), 6.99 (d, J= 8.28 Hz, 1H), 4.35-4.28 (m, 4H), 4.24 (d, J = 14.04 Hz, 1H), 3.54 (d,J = 14.04 Hz, 1H), 2.89-2.81 (m, 1H), 2.58- 2.51 (m, 1H), 2.22 (dd, J =9.56, 8.36 Hz, 1H), 2.00-1.91 (m, 1H), 1.72-1.58 (m, 2H), 1.44-1.33 (m,1H), 1.12 (d, J = 6.04 Hz, 3H). Example ¹H-NMR (500 MHz, DMSO): δ 10.38(s, 1H), 10.18 (s, 1H), Found [M + H]⁺ 176 8.64 (s, 1H), 8.47 (d, J =8.54 Hz, 1H), 8.24 (d, J = 8.91 541.2221 Hz, 1H), 8.14 (dd, J = 7.42,2.60 Hz, 1H), 8.08 (d, J = 8.54 C₃₁H₃₀FN₄O₄ Hz, 1H), 7.71 (d, J = 8.27Hz, 1H), 7.68-7.62 (m, 1H), 7.57- requires 7.53 (m, 1H), 7.52 (d, J =8.27 Hz, 1H), 7.29 (app t, J = 541.2246 10.11 Hz, 1H), 6.99 (d, J = 8.27Hz, 1H), 4.38-4.27 (m, 4H), 4.24 (d, J = 13.93 Hz, 1H), 3.54 (d, J =13.93 Hz, 1H), 2.89-2.82 (m, 1H), 2.57-2.50 (m, 1H), 2.22 (dd, J = 9.56,8.36 Hz, 1H), 1.99-1.90 (m, 1H), 1.72-1.59 (m, 2H), 1.43- 1.33 (m, 1H),1.12 (d, J = 6.03 Hz, 3H). Example ¹H-NMR (500 MHz, DMSO): δ 10.50 (s,1H), 10.29 (s, 1H), Found [M + H]⁺ 177 8.69 (d, J = 1.53 Hz, 1H), 8.50(d, J = 8.39 Hz, 1H), 8.27 598.2809 (dd, J = 8.39, 1.53 Hz, 1H), 8.13(dd, J = 7.29, 2.43 Hz, C₃₄H₃₇FN₅O₄ 1H), 8.09 (d, J = 8.51 Hz, 1H), 7.74(d, J = 8.39 Hz, 1H), requires 7.61-7.66 (m, 1H), 7.57 (d, J = 2.22 Hz,1H), 7.55 (dd, J = 598.2824 8.51, 2.22 Hz, 1H), 7.28 (app t, J = 9.82Hz, 1H), 6.98 (d, J = 8.51 Hz, 1H), 4.35-4.27 (m, 4H), 3.85 (s, 2H),3.09-2.54 (m, 8H), 1.46-0.94 (bs, 9H). Example ¹H-NMR (500 MHz, DMSO): δ10.38 (s, 1H), 10.18 (s, 1H), Found [M + H]⁺ 178 8.65 (d, J = 1.70 Hz,1H), 8.49 (d, J = 8.50 Hz, 1H), 8.25 582.2487 (dd, J = 9.05, 2.55 Hz,1H), 8.14 (dd, J 6.80, 2.55 Hz, 1H), C₃₃H₃₃FN₅O₄ 8.08 (d, J = 9.05 Hz,1H), 7.73 (d, J = 8.50 Hz, 1H), 7.68- requires 7.63 (m, 1H), 7.54 (d, J= 1.70 Hz, 1H), 7.52 (dd, J = 7.65, 582.2511 1.70 Hz, 1H), 7.30 (app t,J = 9.87 Hz, 1H), 6.99 (d, J = 8.50 Hz, 1H), 4.34-4.28 (m, 4H), 3.78 (s,2H), 2.57 (bs, 4H), 2.57 (bs, 4H), 2.44 (bs, 4H), 1.61 (app heptet, J =3.23 Hz, 1H), 0.42-0.37 (m, 2H), 0.29-0.25 (m, 2H). Example ¹H-NMR (500MHz, DMSO): δ 10.39 (s, 1H), 10.19 (s, 1H), Found [M + H]⁺ 179 8.65 (d,J = 1.70 Hz, 1H), 8.49 (d, J = 8.50 Hz, 1H), 8.25 598.2808 (dd, J =8.50, 1.70 Hz, 1H), 8.14 (dd, J = 6.80, 2.55 Hz, C₃₄H₃₇FN₅O₄ 1H), 8.08(d, J = 9.12 Hz, 1H), 7.73 (d, J = 8.50 Hz, 1H), requires 7.68-7.63 (m,1H), 7.54 (d, J = 1.70 Hz, 1H), 7.52 (dd, J = 582.2824 8.50, 2.55 Hz,1H), 7.29 (app t, J = 9.92 Hz, 1H), 6.99 (d, J = 8.50 Hz, 1H), 4.36-4.27(m, 4H), 3.79 (s, 2H), 2.61-2.28 (m, 9H), 1.55-1.38 (m, 1H), 1.35-1.16(m, 1H), 0.91 (bs, 3H), 0.84 (t, J = 7.97 Hz, 3H). Example ¹H-NMR (500MHz, DMSO): δ 10.48 (s, 1H), 10.29 (s, 1H), Found [M + H]⁺ 180 8.68 (d,J = 1.81 Hz, 1H), 8.48 (d, J = 9.06 Hz, 1H), 8.26 582.2489 (dd, J =9.06, 1.81 Hz, 1H), 8.13 (dd, J = 7.25, 2.72 Hz, C₃₃H₃₃FN₅O₄ 1H), 8.05(d, J = 9.06 Hz, 1H), 7.76 (d, J = 8.16 Hz, 1H), requires 7.71-7.66 (m,1H), 7.57 (d, J = 2.72 Hz, 1H), 7.55 (dd, J = 582.2511 9.06, 2.72 Hz,1H), 7.28 (app t, J = 9.97 Hz, 1H), 6.99 (d, J = 9.06 Hz, 1H), 4.34-4.27(m, 5H), 4.03 (d, J = 14.59 Hz, 1H), 3.95 (d, J = 14.59 Hz, 1H),2.87-2.57 (m, 6H), 1.78- 1.58 (m, 3H), 1.01 (t, J = 6.48 Hz, 3H).Example ¹H-NMR (500 MHz, DMSO): δ 10.39 (s, 1H), 10.18 (s, 1H), Found[M + H]⁺ 181 8.64 (d, J = 1.67 Hz, 1H), 8.47 (d, J = 8.37 Hz, 1H), 8.24553.2266 (dd, J = 8.37, 1.67 Hz, 1H), 8.14 (dd, J = 6.69, 2.51 Hz,C₃₂H₃₀FN₄O₄ 1H), 8.06 (d, J = 8.37 Hz, 1H), 7.68-7.64 (m, 1H), 7.63 (d,requires J = 8.37 Hz, 1H), 7.55 (d, J = 2.51 Hz, 1H), 7.52 (dd, J =553.2251 8.37, 2.51 Hz, 1H), 7.29 (app t, J = 10.04 Hz, 1H), 6.99 (d, J= 8.37 Hz, 1H), 4.36-4.27 (m, 4H), 3.83 (s, 2H), 3.24 (s, 4H), 2.07 (t,J = 8.08 Hz, 4H), 1.76 (qn, J = 8.08 Hz, 2H). Example ¹H-NMR (500 MHz,DMSO): δ 10.41 (s, 1H), 10.19 (s, 1H), Found [M + H]⁺ 182 8.66 (d, J =1.49 Hz, 1H), 8.50 (d, J = 8.20 Hz, 1H), 8.27 527.2102 (dd, J = 8.20,1.49 Hz, 1H), 8.14 (dd, J = 6.71, 2.24 Hz, C₃₀H₂₈FN₄O₄ 1H), 8.09 (d, J =8.20 Hz, 1H), 7.67-7.64 (m, 1H), 7.64 (d, requires J = 8.20 Hz, 1H),7.55 (d, J = 1.49 Hz, 1H), 7.52 (dd, J = 527.2095 8.20, 1.49 Hz, 1H),7.29 (app t, J = 9.69 Hz, 1H), 6.99 (d, J = 8.20 Hz, 1H), 4.35-4.28 (m,4H), 4.11 (bs, 2H), 3.72-3.63 (m, 2H), 3.16-3.04 (m, 2H), 2.62 (oct, J =7.43 Hz, 1H), 1.17 (d, J = 7.43 Hz, 3H). Example ¹H-NMR (500 MHz, DMSO):δ 10.40 (s, 1H), 10.18 (s, Found [M + H]⁺ 183 1H), 8.66 (d, J = 1.95 Hz,1H), 8.51 (d, J = 8.47 Hz, 541.2240 1H), 8.26 (dd, J = 8.47, 1.95 Hz,1H), 8.14 (dd, J = C₃₁H₃₀FN₄O₄ 7.16, 2.60 Hz, 1H), 8.08 (d, J = 9.12 Hz,1H), 7.67- requires 7.63 (m, 2H), 7.54 (d, J = 1.95 Hz, 1H), 7.52 (dd, J= 541.2246 8.47, 2.60 Hz, 1H), 7.29 (app t, J = 9.77 Hz, 1H), 6.99 (d, J= 8.47 Hz, 1H), 4.35-4.28 (m, 4H), 4.08 (bs, 2H), 3.22 (bs, 4H), 1.24(s, 6H). Example ¹H-NMR (500 MHz, MeOD): δ 8.58 (d, J = 1.88 Hz, Found[M + H]⁺ 184 1H), 8.47 (d, J = 8.16 Hz, 1H), 8.27 (dd, J = 8.16,584.2693 1.88 Hz, 1H), 8.19 (dd, J = 6.28, 2.51 Hz, 1H), 8.12C₃₃H₃₄FN₅O₄ (d, J = 8.16 Hz, 1H), 7.87 (d, J = 8.16 Hz, 1H), 7.60-requires 7.56 (m, 1H), 7.49 (d, J = 1.88 Hz, 1H), 7.48 (dd, J = 584.26738.16, 1.88 Hz, 1H), 7.22 (app t, J = 9.42 Hz, 1H), 6.94 (d, J = 8.16 Hz,1H), 4.35-4.28 (m, 4H), 4.00 (s, 2H), 2.88-2.78 (m, 8H), 2.63 (q, J =7.61 Hz, 2H), 1.92- 1.85 (m, 2H), 1.11 (t, J = 7.61 Hz, 3H).

Example 185,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-isopropylpiperazin-1-yl)methyl)quinoline-6-carboxamide

N-(3-amino-4-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide(0.1009 g, 0.347 mmol),2-((4-isopropylpiperazin-1-yl)methyl)quinoline-6-carboxylic acidhydrochloride (0.143 g, 0.763 mmol) and EDO (0.166 g, 0.867 mmol) weredissolved in dry DMF (2.5 mL), then pyridine (0.140 mL, 1.734 mmol) wasadded dropwise and the resulting mixture was allowed to stir at roomtemperature for 72 hours. The reaction mixture was poured onto water (5mL) and the precipitate was washed several times with water and Et₂O toafford the crude product as a pale yellow solid, which was purified viaflash column chromatography on silica gel in gradient (from 0 to 10%MeOH in DCM) to afford the title compound as an orange solid (0.050 g,25%). ¹H-NMR (500 MHz, DMSO): δ 10.41 (bs, 1H), 10.21 (bs, 1H), 8.65 (s,1H), 8.49 (d, J=8.78 Hz, 1H), 8.25 (dd, J=8.78, 1.88 Hz, 1H), 8.14 (dd,J=6.90, 2.51 Hz, 1H), 8.08 (d, J=8.78 Hz, 1H), 7.73 (d, J=8.78 Hz, 1H),7.68-7.63 (m, 1H), 7.55 (d, J=2.51 Hz, 1H), 7.52 (dd, J=8.78, 1.88 Hz,1H), 7.29 (app t, J=9.28 Hz, 1H), 6.99 (d, J=8.78 Hz, 1H), 4.36-4.27 (m,4H), 3.79 (bs, 2H), 3.15-2.34 (m, 9H), 0.99 (bs, 6H). HRMS (ESI⁺): Found[M+H]⁺ 584.2636 C₃₃H₃₅N₅O₄ requires 584.2668.

The following compounds were synthesised according to the procedure forExample 185, by substituting the appropriate carboxylic acid for2-((4-isopropylpiperazin-1-yl)methyl)quinoline-6-carboxylic acidhydrochloride.

-   Example 186,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(3-(piperidin-1-yl)propoxy)quinoline-6-carboxamide-   Example 187,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(3-(pyrrolidin-1-yl)propoxy)quinoline-6-carboxamide-   Example 188,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide-   Example 189,    N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-(3-(piperidin-1-yl)propoxy)quinoline-6-carboxamide-   Example 190,    (rac)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((2-methylpyrrolidin-1-yl)methyl)quinoline-6-carboxamide

TABLE F Compound 1H NMR Mass Spec Example ¹H-NMR (500 MHz, DMSO): δ10.32 (bs, 1H), 10.19 (bs, Found [M + H]⁺ 186 1H), 8.59 (d, J = 1.76 Hz,1H), 8.39 (d, J = 8.79 Hz, 1H), 585.2485 8.22 (dd, J 8.79, 1.76 Hz, 1H),8.13 (dd, J = 7.03 Hz, 2.34 C₃₃H₃₄FN₄O₅ Hz, 1H), 7.86 (d, J = 8.79 Hz,1H), 7.67-7.62 (m, 1H), 7.55 requires (d, J = 1.76 Hz, 1H), 7.52 (dd, J= 8.21, 1.76 Hz, 1H), 7.28 585.2508. (app t, J = 9.96 Hz, 1H), 7.11 (d,J = 8.90 Hz, 1H), 6.99 (d, J = 8.90 Hz, 1H), 4.51 (t, J = 6.29 Hz, 2H),4.34-4.28 (m, 4H), 3.16-2.65 (m, 4H), 2.36-1.30 (m, 10H). Example ¹H-NMR(500 MHz, DMSO): δ 10.32 (bs, 1H), 10.19 (bs, Found [M + H]⁺ 187 1H),8.59 (d, J = 2.21 Hz, 1H), 8.41 (d, J = 8.84 Hz, 1H), 571.2321 8.23 (dd,J = 8.84, 2.21 Hz, 1H), 8.13 (dd, J = 8.84, 2.21 C₃₂H₃₂FN₄O₅ Hz, 1H),7.87 (d, J = 8.84 Hz, 1H), 7.66-7.61 (m, 1H), 7.55 requires (d, J = 2.21Hz, 1H), 7.52 (dd, J = 8.11, 2.21 Hz, 1H), 7.29 571.2351. (app t, J =10.23 Hz, 1H), 7.12 (d, J = 8.84 Hz, 1H), 6.99 (d, J = 8.84 Hz, 1H),4.53 (t, J = 5.57 Hz, 2H), 4.34-4.28 (m, 4H), 3.41-2.66 (m, 6H),2.21-2.09 (m, 2H), 1.93-1.80 (m, 4H). Example ¹H-NMR (500 MHz, MeOD): δ8.48 (d, J = 2.04 Hz, 1H), Found [M + H]⁺ 188 8.29 (d, J = 8.85 Hz, 1H),8.20 (dd, J = 8.17, 2.04 Hz, 1H), 557.2196 8.17 (dd, J = 6.81, 2.72 Hz,1H), 7.92 (d, J = 8.17 Hz, 1H), C₃₁H₃₀FN₄O₅ 7.62-7.56 (m, 1H), 7.50 (d,J = 2.04 Hz, 1H), 7.48 (dd, J = requires 8.17, 2.04 Hz, 1H), 7.23 (appt, J = 9.79 Hz, 1H), 7.09 (d, 557.2195. J = 8.85 Hz, 1H), 6.96 (d, J =8.17 Hz, 1H), 4.70 (t, J = 5.32 Hz, 2H), 4.36-4.28 (m, 4H), 3.08 (t, J =5.25 Hz, 2H), 2.84-2.76 (m, 4H), 1.91-1.85 (m, 4H). Example ¹H-NMR (500MHz, DMSO): δ 10.29 (s, 1H), 10.26 (s, 1H), Found [M + H]⁺ 189 8.60 (bs,1H), 8.41 (d, J = 9.19 Hz, 1H), 8.24 (d, J = 8.49 601.2200 Hz, 1H), 8.13(d, J = 2.12 Hz, 1H), 7.87 (d, J = 8.49 Hz, C₃₃H₃₄ClN₄O₅ 1H), 7.74 (dd,J = 9.19, 2.12 Hz, 1H), 7.56 (d, J = 2.12 Hz, requires 1H), 7.55-7.50(m, 2H), 7.11 (d, J = 8.49 Hz, 1H), 6.99 (d, 601.2212. J = 8.49 Hz, 1H),4.51 (t, J = 6.52 Hz, 2H), 4.35-4.27 (m, 4H), 3.08 (t, J = 5.25 Hz, 2H),2.28-1.96 (m, 4H), 1.84-1.32 (m, 8H). Example ¹H-NMR (500 MHz, DMSO): δ10.39 (s, 1H), 10.19 (s, 1H), Found [M + H]⁺ 190 8.64 (d, J = 1.48 Hz,1H), 8.48 (d, J = 8.87 Hz, 1H), 8.24 541.2236 (dd, J = 8.87, 2.22 Hz,1H), 8.13 (dd, J = 6.65, 2.22 Hz, C₃₁H₃₀FN₄O₄ 1H), 8.08 (d, J = 8.87 Hz,1H), 7.68-7.63 (m, 1H), 7.55 (d, requires J = 2.22 Hz, 1H), 7.48 (dd, J= 8.87, 2.22 Hz, 1H), 7.29 541.2246. (app t, J = 9.61 Hz, 1H), 6.99 (d,J = 8.87 Hz, 1H), 4.34- 4.28 (m, 4H), 4.24 (d, J = 13.83 Hz, 1H), 3.53(d, J = 13.83 Hz, 1H), 2.89-2.83 (m, 1H), 2.57-2.48 (m, 1H), 2.22 (q, J= 8.80 Hz, 1H), 2.00-1.91 (m, 1H), 1.71-1.59 (m, 2H), 1.43- 1.34 (m,1H), 1.11 (d, J = 5.03 Hz, 3H).

Compound 230, methyl 2-formylquinoline-6-carboxylate

To a solution of 2-methylquinoline-6-carboxylic acid (1.5 g, 8.01 mmol)in dry methanol (18 mL) under argon at room temperature, HCl in dioxane(8.01 mL, 32.1 mmol) was added dropwise and the resulting mixture washeated at 85° C. for 7 hours. Then it was cooled, concentrated, dilutedwith ethyl acetate and washed with NaOH 1N (2×20 mL), water (1×20 mL)and brine (1×20 mL). Dried over Na₂SO₄, filtered and concentrated undervacuum to afford the crude productmethyl-2-methylquinoline-6-carboxylate as a pink solid (1.44 g, 89%)which was carried onto the next step without purification. To asuspension of selenium dioxide (0.873 g, 7.87 mmol) in dry dioxane (11mL) under argon at room temperaturemethyl-2-methylquinoline-6-carboxylate (1.44 g, 7.16 mmol) was added inone portion and the resulting suspension was allowed to stir at 80° C.for 18 hours. The reaction was allowed to cool to room temperature,filtered through Celite and concentrated under vacuum to afford anorange solid as crude product which was purified via flash columnchromatography on silica gel in gradient from 10 to 20% ethyl acetate inpetroleum ether to afford the clean product as a pale yellow solid (1.28g, 83%). ¹H-NMR (500 MHz, CDCl₃): δ 10.26 (d, J=0.58 Hz, 1H), 8.68 (d,J=1.62 Hz, 1H), 8.45 (d, J=8.71 Hz, 1H), 8.42 (dd, J=8.71, 1.62 Hz, 1H),8.32 (d, J=8.71 Hz, 1H), 8.11 (d, J=8.23 Hz, 1H), 4.04 (s, 3H). HRMS(ESI⁺): Found [M+H]⁺ 216.0658 C₁₂H₁₀NO₃ requires 216.0660.

Compound 231, methyl2-((4-isopropylpiperazin-1-yl)methyl)quinoline-6-carboxylate

To a solution of methyl-2-formylquinoline-6-carboxylate (0.20 g, 0.929mmol) in dry DCM, 1-isopropylpiperazine (0.399 mL, 2.79 mmol) was addeddropwise at room temperature and the resulting mixture was allowed tostir under an inert argon atmosphere for 2.5 hours. Then sodiumtriacetoxyborohydride (0.591 g, 2.79 mmol) was added in one portion andthe resulting mixture was allowed to stir overnight at room temperature.The reaction mixture was diluted with DCM (20 mL) and quenched withNaHCO₃ (20 mL). The aqueous phase was extracted with DCM (3×10 mL) andthe combined organic layers were dried to afford a yellow-orange solidas crude product (322 mg, 106%) which was carried through the next stepwithout purification. ¹H-NMR (500 MHz, CDCl₃): δ 8.55 (d, J=1.93 Hz,1H), 8.27 (dd, J=8.87, 1.93 Hz, 1H), 8.20 (d, J=8.87 Hz, 1H), 8.09 (d,J=8.87 Hz, 1H), 7.70 (d, J=8.87 Hz, 1H), 3.98 (s, 3H), 3.86 (s, 2H),2.26 (heptet, J=6.75 Hz, 1H), 2.67-2.52 (m, 8H), 1.05 (d, J=6.75 Hz,6H). HRMS (ESI⁺): Found [M+H]⁺ 328.2031 C₁₉H₂₆N₃O₂ requires 328.2020.

Compound 232,2-((4-isopropylpiperazin-1-yl)methyl)quinoline-6-carboxylic acid

To a solution of methyl2-((4-isopropylpiperazin-1-yl)methyl)quinolone-6-carboxylate (0.32 g,0.977 mmol) in THF (6 mL), sodium hydroxide aqueous solution (2.443 mL,4.89 mmol) was added dropwise at 20° C. and methanol (2.4 mL) was addedto increase the miscibility of the two phases. The resulting red-brownsolution was allowed to stir at room temperature for 2 hours after whichit was concentrated under reduced pressure to remove the organicsolvents and the aqueous layer was acidified with HCl 1N (pH 3) and thenwashed with ethyl acetate (3×5 mL). The aqueous phase is concentratedunder reduced pressure to afford a salmon solid as crude product (0.306g, 100%) which was carried onto the next step without purification.¹H-NMR (500 MHz, DMSO): δ_(H) 11.99 (bs, 1H), 8.73 (d, J=1.47 Hz, 1H),8.71 (d, J=8.01 Hz, 1H), 8.27 (dd, J=8.84, 1.97 Hz, 1H), 8.18 (d, J=8.84Hz, 1H), 7.89 (d, J=8.35 Hz, 1H), 4.69 (bs, 2H), 2.79-2.46 (m, 9H), 1.29(d, J=6.74 Hz, 6H). HRMS (ESI⁺): Found [M+H]⁺ 314.1868 C₁₈H₂₄N₃O₂requires 314.1863.

Compound 233, N-(2-chloro-5-nitrophenyl)-2-methylquinoline-6-carboxamide

To a suspension of 2-methylquinoline-6-carboxylic acid (1.5 g, 8.01mmol) in dry DCM (40 mL), DMF (1.401 μl, 0.018 mmol) and oxalyl chloride(0.740 mL, 8.74 mmol) were added dropwise and the resulting greensolution was allowed to stir at 20° C. for 3 hours after which it wasconcentrated under vacuum to afford a dry pale green solid. The solidwas dissolved in pyridine (40.0 mL) and 2-chloro-5-nitroaniline (1.257g, 7.28 mmol) was added in one portion. The resulting dark yellowsuspension was allowed to stir for 2 hours after which it was pouredonto water and the yellow precipitate was filtered and washed severaltimes with water, Et₂O and finally with a minimum amount of DCM toafford the crude product as a yellow solid which does not requirefurther purification (2.20 g, 88%). ¹H-NMR (500 MHz, DMSO): δ 10.59 (s,1H), 8.65 (d, J=1.99 Hz, 1H), 8.60 (d, J=2.66 Hz, 1H), 8.44 (d, J=8.64Hz, 1H), 8.25 (dd, J=8.64, 1.99 Hz, 1H), 8.15 (dd, J=8.64, 2.66 Hz, 1H),8.06 (d, J=8.64 Hz, 1H), 7.91 (d, J=8.64 Hz, 1H), 7.55 (d, J=7.98 Hz,1H), 2.71 (s, 3H). HRMS (ESI⁺): Found [M+H]⁺ 342.0646 C₁₇H₁₃ClN₃O₃requires 342.0640.

Compound 234, N-(5-amino-2-chlorophenyl)-2-methylquinoline-6-carboxamide

To a solution ofN-(2-chloro-5-nitrophenyl)-2-methylquinoline-6-carboxamide in water(7.00 mL) and EtOH (21 mL), ammonium chloride (2.410 g, 45.1 mmol) andiron powder (2.52 g, 45.1 mmol) were added and the resulting suspensionwas allowed to stir at 90° C. for 1 hour. The reaction mixture wasallowed to warm to room temperature, diluted with MeOH and DCM andfiltered through a pad of Celite. The resulting filtrate wasconcentrated under vacuum to afford a light brown solid as crudeproduct, which was taken directly onto the next step without any furtherpurification (2.00 g, 100%). ¹H-NMR (500 MHz, DMSO): δ 9.96 (s, 1H),8.58 (d, J=2.18 Hz, 1H), 8.41 (d, J=8.72 Hz, 1H), 8.21 (dd, J=8.72, 2.18Hz, 1H), 8.02 (d, J=8.72 Hz, 1H), 7.53 (d, J=7.63 Hz, 1H), 7.15 (d,J=8.72 Hz, 1H), 6.87 (d, J=2.18 Hz, 1H), 6.50 (dd, J=8.72, 2.18 Hz, 1H),5.41 (bs, 2H), 2.70 (s, 3H). HRMS (ESI⁺): Found [M+H]⁺ 312.0902C₁₇H₁₅ClN₃O requires 312.0898.

Compound 235,N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-methylquinoline-6-carboxamide

To a suspension of 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid(1.271 g, 7.06 mmol) in dry DCM (20 mL), DMF (1.234 μl, 0.016 mmol) andoxalyl chloride (0.651 mL, 7.70 mmol) were added dropwise and theresulting green solution was allowed to stir at 20° C. for 3 hours afterwhich it was concentrated under vacuum to afford a dry pale green solid.The solid was dissolved in pyridine (20.00 mL) andN-(5-amino-2-chlorophenyl)-2-methylquinoline-6-carboxamide (2.00 g, 6.42mmol) was added in one portion. The resulting dark yellow suspension wasallowed to stir for 2 hours after which it was poured onto water and theyellow precipitate was filtered and washed several times with water,Et₂O and finally with a minimum amount of DCM to afford the crudeproduct as a pale yellow solid which does not require furtherpurification (1.86 g, 61%). ¹H-NMR (500 MHz, DMSO): δ 10.31 (s, 1H),10.27 (s, 1H), 8.63 (d, J=1.47 Hz, 1H), 8.43 (d, J=8.81 Hz, 1H), 8.25(dd, J=8.81, 2.20 Hz, 1H), 8.14 (d, J=2.20 Hz, 1H), 8.04 (d, J=8.81 Hz,1H), 7.75 (dd, J=8.81, 2.94 Hz, 1H), 7.58-7.49 (m, 4H), 7.00 (d, J=8.81Hz, 1H), 4.37-4.26 (m, 4H), 2.71 (s, 3H). HRMS (ESI⁺): Found [M+H]⁺474.1210 C₂₆H₂₁ClN₃O₄ requires 474.1215.

Compound 236,N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-formylquinoline-6-carboxamide

A solution ofN-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-methylquinoline-6-carboxamide(0.500 g, 1.055 mmol) and selenium dioxide (0.129 g, 1.161 mmol) in dryDMF (12.00 mL) and dioxane (12.00 mL) was heated at 152° C. for 2 hafter which a further portion of selenium dioxide (0.129 g, 1.161 mmol)was added and the reaction mixture was allowed to stir at 152° C. for 1h. Then the reaction mixture was allowed to cool to room temperature andit was diluted with DCM and filtered through a pad of Celite. Thefiltrate was concentrated under vacuum to afford the crude product as ayellow solid which was taken directly onto the next step without anyfurther purification (0.515 g, 100%). ¹H-NMR (500 MHz, DMSO): δ 10.45(s, 1H), 10.40 (s, 1H), 10.17 (s, 1H), 8.81-8.79 (m, 2H), 8.42-8.34 (m,2H), 8.19 (app t, J=7.47 Hz, 1H), 8.09 (d, J=8.13 Hz, 1H), 7.79-7.74 (m,2H), 7.55 (d, J=1.99 Hz, 1H), 7.52 (dd, J=8.13, 1.99 Hz, 1H), 6.99 (d,J=9.04 Hz, 1H), 4.36-4.26 (m, 4H). HRMS (ESI⁺): Found [M+H]⁺ 488.1012C₂₆H₁₉ClN₃O₅ requires 488.1013.

Example 191,2-((4-(tert-butyl)piperazin-1-yl)methyl)-N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide

A solution ofN-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-formylquinoline-6-carboxamide(0.300 g, 0.615 mmol) and 1-(tert-butyl)piperazine in dry DCM (5 mL) wasallowed to stir at 20° C. for 12 h, after which sodiumtriacetoxyborohydride (0.391 g, 1.845 mmol) was added in one portion andthe resulting mixture was allowed to stir at 20° C. for 2 h. Thereaction was quenched with NaHCO₃ saturated aqueous solution (5 mL) andextracted with a DCM/MeOH 9/1 mixture (3×5 mL). The crude product (paleyellow solid) was purified via flash column chromatography on silica gelin gradient from 0 to 10% MeOH in DCM followed by water wash and Et₂Otrituration to afford the desired product as a beige solid (0.060 g,16%). ¹H-NMR (500 MHz, DMSO): δ 10.34 (s, 1H), 10.29 (s, 1H), 8.66 (d,J=1.56 Hz, 1H), 8.50 (d, J=8.60 Hz, 1H), 8.26 (dd, J=8.60, 2.35 Hz, 1H),8.14 (d, J=2.35 Hz, 1H), 8.09 (d, J=8.60 Hz, 1H), 7.77-7.72 (m, 2H),7.56 (d, J=2.35 Hz, 1H), 7.54 (d, J=1.56 Hz, 1H), 7.53 (dd, J=7.82, 2.35Hz, 1H), 7.00 (d, J=8.60 Hz, 1H), 4.35-4.27 (m, 4H), 3.79 (s, 2H),2.79-2.29 (m, 8H), 1.03 (bs, 9H). HRMS (ESI⁺): Found [M+H]⁺ 614.2502C₃₄H₃₇ClN₅O₄ requires 614.2529.

The following compounds were synthesised according to the procedure forExample 191, by substituting the appropriate amine for1-(tert-butyl)piperazine.

-   Example 192,    N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-(piperazin-1-ylmethyl)quinoline-6-carboxamide-   Example 193,    2-((4-(sec-butyl)piperazin-1-yl)methyl)-N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide-   Example 194,    N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((4-cyclopropylpiperazin-1-yl)methyl)quinoline-6-carboxamide-   Example 195,    N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((4-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide-   Example 196,    N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide-   Example 197,    N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((4-isopropylpiperazin-1-yl)methyl)quinoline-6-carboxamide-   Example 198,    N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-(pyrrolidin-1-ylmethyl)quinoline-6-carboxamide-   Example 199,    2-(azetidin-1-ylmethyl)-N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide-   Example 200,    N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((3-methylazetidin-1-yl)methyl)quinoline-6-carboxamide-   Example 201,    N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((3,3-dimethylazetidin-1-yl)methyl)quinoline-6-carboxamide

TABLE G Compound 1H NMR Mass Spec Example ¹H-NMR (500 MHz, DMSO): δ10.38 (s, 1H), 10.33 (s, 1H), Found [M + H]⁺ 192 9.01 (bs, 1H), 8.69 (d,J = 1.65 Hz, 1H), 8.53 (d, J = 8.27 558.1877 Hz, 1H), 8.28 (dd, J =8.27, 1.65 Hz, 1H), 8.16 (dd, J = C₃₀H₂₉ClN₅O₄ 2.48 Hz, 1H), 8.10 (d, J= 8.27 Hz, 1H), 7.78-7.72 (m, 2H), requires 7.57 (d, J = 2.48 Hz, 1H),7.54 (dd, J = 8.27, 2.48 Hz, 1H), 558.1903 7.53 (d, J = 8.61 Hz, 1H),6.99 (d, J = 8.27 Hz, 1H), 4.35- 4.28 (m, 4H), 3.88 (s, 2H), 3.12-3.04(m, 4H), 2.73-2.68 (m, 4H). Example ¹H-NMR (500 MHz, DMSO): δ 10.32 (s,1H), 10.27 (s, 1H), Found [M + H]⁺ 193 8.66 (d, J = 1.60 Hz, 1H), 8.50(d, J = 8.43 Hz, 1H), 8.26 614.2495 (dd, J = 8.43, 1.60 Hz, 1H), 8.15(d, J = 2.36 Hz, 1H), 8.09 C₃₄H₃₇ClN₅O₄ (d, J = 8.43 Hz, 1H), 7.75 (dd,J = 8.43, 2.36 Hz, 1H), 7.74 requires (d, J = 8.43 Hz, 1H), 7.55 (d, J =2.36 Hz, 1H), 7.54 (d, J = 614.2529 1.60 Hz, 1H), 7.52 (dd, J = 7.88,2.36 Hz, 1H), 7.00 (d, J = 8.43 Hz, 1H), 4.35-4.27 (m, 4H), 3.81 (s,2H), 2.87-2.17 (m, 9H), 1.51 (bs, 1H), 1.28 (bs, 1H), 0.95 (bs, 3H),0.85 (t, J = 7.65 Hz, 3H). Example ¹H-NMR (500 MHz, DMSO): δ 10.32 (s,1H), 10.27 (s, 1H), Found [M + H]⁺ 194 8.65 (s, 1H), 8.50 (d, J = 7.87Hz, 1H), 8.26 (d, J = 7.87 598.2210 Hz, 1H), 8.15 (d, J = 1.83 Hz, 1H),8.09 (d, J = 7.87 Hz, C₃₃H₃₃ClN₅O₄ 1H), 7.77-7.71 (m, 2H), 7.57-7.49 (m,3H), 7.00 (d, J = requires 7.87 Hz, 1H), 4.36-4.24 (m, 4H), 3.78 (s,2H), 2.57 (bs, 598.2216 4H), 2.43 (bs, 4H), 1.63-1.58 (m, 1H), 0.42-0.37(m, 2H), 0.30-0.24 (m, 2H). Example ¹H-NMR (500 MHz, DMSO): δ 10.32 (s,1H), 10.23 (s, 1H), Found [M + H]⁺ 195 8.65 (s, 1H), 8.48 (d, J = 8.24Hz, 1H), 8.29 (dd, J = 8.24 572.2031 Hz, 1H), 8.14 (s, 1H), 8.07 (d, J =8.24 Hz, 1H), 7.71 (d, J = C₃₁H₃₁ClN₅O₄ 8.24 Hz, 2H), 7.57-7.43 (m, 3H),7.00 (d, J = 8.24 Hz, requires 1H), 4.36-4.22 (m, 4H), 3.79 (s, 2H),2.47-2.23 (m, 8H), 572.2059 2.17 (s, 3H). Example ¹H-NMR (500 MHz,DMSO): δ 10.32 (s, 1H), 10.27 (s, 1H), Found [M + H]⁺ 196 8.65 (s, 1H),8.50 (d, J = 8.56 Hz, 1H), 8.26 (dd, J = 8.56, 586.2189 1.56 Hz, 1H),8.14 (d, J = 2.34 Hz, 1H), 8.09 (d, J = 8.56 C₃₂H₃₃ClN₅O₄ Hz, 1H),7.77-7.71 (m, 2H), 7.57-7.50 (m, 3H), 7.00 (d, J = requires 8.56 Hz,1H), 4.35-4.28 (m, 4H), 3.80 (s, 2H), 2.49-2.18 586.2216 (m, 10H), 0.99(t, J = 6.97 Hz, 3H). Example ¹H-NMR (500 MHz, DMSO): δ 10.33 (bs, 1H),10.27 (bs, Found [M + H]⁺ 197 1H), 8.66 (d, J = 1.38 Hz, 1H), 8.50 (d, J= 8.25 Hz, 1H), 600.2336 8.26 (dd, J = 8.25, 1.38 Hz, 1H), 8.15 (d, J =2.75 Hz, 1H), C₃₃H₃₅ClN₅O₄ 8.09 (d, J = 8.94 Hz, 1H), 7.76-7.61 (m, 2H),7.56-7.50 (m, requires 3H), 7.00 (d, J = 8.25 Hz, 1H), 4.34-4.27 (m,4H), 3.80 (bs, 600.2372 2H), 2.76-2.40 (m, 9H), 0.99 (bs, 6H). Example¹H-NMR (500 MHz, DMSO): δ 10.32 (s, 1H), 10.27 (s, 1H), Found [M + H]⁺198 8.65 (s, 1H), 8.49 (d, J = 7.98 Hz, 1H), 8.26 (dd, J = 7.98,543.1778 2.28 Hz, 1H), 8.14 (d, J = 2.28 Hz, 1H), 8.09 (d, J = 7.98C₃₀H₂₈ClN₄O₄ Hz, 1H), 7.77-7.70 (m, 2H), 7.56-7.50 (m, 3H), 7.00 (d, J =requires 7.98 Hz, 1H), 4.35-4.28 (m, 4H), 3.92 (s, 2H), 2.57-2.52543.1794 (m, 4H), 1.77-1.70 (m, 4H). Example ¹H-NMR (500 MHz, DMSO): δ10.35 (s, 1H), 10.31 (s, 1H), Found [M + H]⁺ 199 8.66 (d, J = 2.16 Hz,1H), 8.49 (d, J = 8.65 Hz, 1H), 8.27 529.1616 (dd, J = 8.65, 2.16 Hz,1H), 8.14 (d, J = 2.16 Hz, 1H), 8.08 C₂₉H₂₆ClN₄O₄ (d, J = 8.65 Hz, 1H),7.76 (dd, J = 8.65, 2.16 Hz, 1H), 7.65 requires (d, J = 7.62 Hz, 1H),7.58-7.51 (m, 3H), 6.99 (d, J = 8.65 529.1637 Hz, 1H), 4.35-4.27 (m,4H), 3.91 (s, 2H), 3.39-3.27 (m, 4H), 2.06 (qn, J = 7.10 Hz, 2H).Example ¹H NMR (500 MHz, Chloroform-d) δ 8.63 (br s, 1H), 8.58 Found[M + H]⁺ 200 (d, J = 2.5 Hz, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.28 (d, J =543.1769 8.5 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.16 (dd, J = 8.8, 2.0C₃₀H₂₈ClN₄O₄ Hz, 1H), 7.98 (dd, J = 8.8, 2.4 Hz, 2H), 7.64 (d, J = 8.5Hz, requires 1H), 7.46 (s, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.39 (dd, J =543.1794 8.4, 2.2 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.36-4.30 (m, 4H),3.99 (s, 2H), 3.64 (t, J = 7.5 Hz, 2H), 2.95 (t, J = 7.2 Hz, 2H),2.75-2.62 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H). Example ¹H-NMR (500 MHz,DMSO): δ 10.35 (s, 1H), 10.27 (s, 1H), Found [M + H]⁺ 201 8.68 (d, J =2.1 Hz, 1H), 8.55 (d, J = 8.5 Hz, 1H), 8.29 (dd, 557.1963 J = 8.8, 2.0Hz, 1H), 8.18-8.08 (m, 2H), 7.74 (dd, J = 8.8, C₃₁H₃₀N₄O₄Cl 2.5 Hz, 1H),7.65 (d, J = 8.5 Hz, 1H), 7.58-7.48 (m, 3H), requires 7.00 (d, J = 8.4Hz, 1H), 4.61-4.01 (m, 6H), 3.23 (brs, 557.1956. 4H), 1.27 (s, 6H).

Compound 237, N-(2-bromo-5-nitrophenyl)-2-methylquinoline-6-carboxamide

To a suspension of 2-methylquinoline-6-carboxylic acid (1.5 g, 8.01mmol) in dry DCM (20 mL), DMF (1.114 μl, 0.014 mmol) and oxalyl chloride(0.588 mL, 6.95 mmol) were added dropwise and the resulting greensolution was allowed to stir at 20° C. for 3 hours after which it wasconcentrated under vacuum to afford a dry pale green solid. The solidwas dissolved in pyridine (20.0 mL) and 2-bromo-5-nitroaniline (1.257 g,5.79 mmol) was added in one portion. The resulting dark yellowsuspension was allowed to stir for 2 hours after which it was pouredonto water and the yellow precipitate was filtered and washed severaltimes with water, Et₂O and finally with a minimum amount of DCM toafford the crude product as a yellow solid which does not requirefurther purification (2.47 g, 110%). ¹H-NMR (500 MHz, DMSO): δ 10.56 (s,1H), 8.65 (d, J=1.78 Hz, 1H), 8.52 (app t, J=1.78 Hz, 1H), 8.44 (d,J=8.32 Hz, 1H), 8.26 (dd, J=8.92, 1.78 Hz, 1H), 8.09-8.05 (m, 3H), 7.55(d, J=8.32 Hz, 1H), 2.71 (s, 3H). HRMS (ESI⁺): Found [M+H]⁺ 386.0129C₁₇H₁₃BrN₃O₃ requires 386.0135.

Compound 238, N-(5-amino-2-bromophenyl)-2-methylquinoline-6-carboxamide

To a solution ofN-(2-bromo-5-nitrophenyl)-2-methylquinoline-6-carboxamide (2.00 g, 5.18mmol) in water (7.00 mL) and EtOH (21 mL), ammonium chloride (1.939 g,36.3 mmol) and iron powder (2.025 g, 36.3 mmol) were added and theresulting suspension was allowed to stir at 90° C. for 1 hour. Thereaction mixture was allowed to cool to room temperature, diluted withMeOH and DCM and filtered through a pad of Celite. The resultingfiltrate was concentrated under vacuum to afford a light brown solid ascrude product, which was taken directly onto the next step without anyfurther purification (1.80 g, 98%). ¹H-NMR (500 MHz, DMSO): δ 9.94 (s,1H), 8.59 (d, J=1.76 Hz, 1H), 8.40 (d, J=8.78 Hz, 1H), 8.22 (dd, J=8.78,1.76 Hz, 1H), 8.02 (d, J=8.78 Hz, 1H), 7.52 (d, J=8.78 Hz, 1H), 7.28 (d,J=8.78 Hz, 1H), 6.86 (d, J=1.76 Hz, 1H), 6.45 (dd, J=8.78, 1.76 Hz, 1H),5.40 (bs, 2H), 2.70 (s, 3H). HRMS (ESI⁺): Found [M+H]⁺ 358.0369C₁₇H₁₅BrN₃O requires 358.0374.

Compound 239,N-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-methylquinoline-6-carboxamide

To a suspension of 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid(1.001 g, 5.56 mmol) in dry DCM (20 mL), DMF (0.972 μl, 0.013 mmol) andoxalyl chloride (0.513 mL, 6.06 mmol) were added dropwise and theresulting green solution was allowed to stir at 20° C. for 3 hours afterwhich it was concentrated under vacuum to afford a dry pale green solid.The solid was dissolved in pyridine (20.00 mL) andN-(5-amino-2-bromophenyl)-2-methylquinoline-6-carboxamide (1.80 g, 5.05mmol) was added in one portion. The resulting dark yellow suspension wasallowed to stir for 72 hours after which it was poured onto water. Theyellow precipitate was filtered and washed several times with water,Et₂O and finally with a minimum amount of DCM to afford the crudeproduct as a pale yellow solid which does not require furtherpurification (2.11 g, 81%). ¹H-NMR (500 MHz, DMSO): δ 10.29 (s, 1H),10.27 (s, 1H), 8.63 (s, 1H), 8.42 (d, J=9.11 Hz, 1H), 8.25 (d, J=7.29Hz, 1H), 8.10 (s, 1H), 8.05 (d, J=8.20 Hz, 1H), 7.69 (bs, 2H), 7.58-7.49(m, 3H), 6.99 (d, J=9.11 Hz, 1H), 4.37-4.27 (m, 4H), 2.71 (s, 3H). HRMS(ESI⁺): Found [M+H]⁺ 520.0723 C₂₆H₂₁BrN₃O₄ requires 520.0693.

Compound 240,N-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-formylquinoline-6-carboxamide

A solution ofN-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-methylquinoline-6-carboxamide(1.00 g, 1.929 mmol) and selenium dioxide (0.235 g, 2.122 mmol) in dryDMF (4.00 mL) and dioxane (12.00 mL) was heated at 152° C. for 1 h. Thereaction mixture was allowed to cool to room temperature and it wasdiluted with DCM and filtered through a pad of Celite. The filtrate wasconcentrated under vacuum to afford the crude product as a yellow solidwhich was taken directly onto the next step without any furtherpurification (1.00 g, 97%). ¹H-NMR (500 MHz, DMSO): δ 10.47 (s, 1H),10.28 (s, 1H), 10.17 (d, J=0.53 Hz, 1H), 8.81-8.77 (m, 2H), 8.42-8.36(m, 2H), 8.13-8.11 (m, 1H), 8.09 (d, J=8.38 Hz, 1H), 7.70 (d, J=1.08 Hz,2H), 7.55 (d, J=2.15 Hz, 1H), 7.52 (dd, J=8.60, 2.15 Hz, 1H), 7.00 (d,J=8.60 Hz, 1H), 4.36-4.23 (m, 4H). HRMS (ESI⁺): Found [M+H]⁺ 532.0550C₂₆H₁₉BrN₃O₅ requires 532.0503.

Compound 241,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-formylquinoline-6-carboxamide

A solution ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methylquinoline-6-carboxamide(0.165 g, 0.364 mmol) and selenium dioxide (0.444 g, 0.400 mmol) in drydioxane (0.6 mL) and dry DMF (0.6 mL) was heated at 152° C. for 1 hafter which the reaction mixture was allowed to cool to roomtemperature, diluted with DCM and filtered through a pad of Celite. Thefiltrate was concentrated under vacuum to afford the crude product as abrown solid which was taken directly onto the next step without anyfurther purification (0.17 g, 100%). ¹H-NMR (500 MHz, DMSO): δ 10.29 (s,1H), 10.17 (s, 1H), 10.09 (s, 1H), 8.81-8.77 (m, 1H), 8.41 (dd, J=8.29,1.66 Hz, 1H), 8.36 (d, J=8.29 Hz, 1H), 8.17-8.12 (m, 1H), 8.08 (d,J=9.12 Hz, 1H), 7.90 (d, J=2.49 Hz, 1H), 7.58 (dd, J=8.29, 2.49 Hz, 1H),7.54 (d, J=2.49 Hz, 1H), 7.52 (dd, J=8.29, 2.49 Hz, 1H), 7.25 (d, J=8.29Hz, 1H), 6.98 (d, J=8.29 Hz, 1H), 4.35-4.28 (m, 4H), 2.31 (s, 3H).

Example 202,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((4-isopropylpiperazin-1-yl)methyl)quinoline-6-carboxamide

To a solution ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-formylquinoline-6-carboxamide(0.170 g, 0.364 mmol) in dry DCM (5 mL), 1-isopropylpiperazine (0.156mL, 1.091 mmol) was added dropwise and the resulting mixture was allowedto stir at 20° C. for 2.5 hours, after which sodiumtriacetoxyborohydride (0.231 g, 1.091 mmol) was added in one portion andthe resulting mixture was allowed to stir at 20° C. for 12 h. Thereaction was diluted with DCM (5 mL), quenched with NaHCO₃ saturatedaqueous solution (10 mL) and extracted with a DCM/MeOH 9/1 mixture (3×5mL). The crude product (brown oil) was purified via flash columnchromatography on silica gel in gradient from 0 to 10% MeOH in DCMfollowed by water wash and Et₂O trituration to afford the desiredproduct as a pale yellow solid (0.030 g, 14%). ¹H-NMR (500 MHz, DMSO): δ10.15 (s, 1H), 10.07 (s, 1H), 8.63 (d, J=1.42 Hz, 1H), 8.49 (d, J=8.51Hz, 1H), 8.26 (dd, J=9.22, 1.42 Hz, 1H), 8.08 (d, J=8.51 Hz, 1H), 7.88(d, J=2.13 Hz, 1H), 7.72 (d, J=8.51 Hz, 1H), 7.59 (dd, J=8.51, 2.13 Hz,1H), 7.54 (d, J=1.42 Hz, 1H), 7.51 (d, J=8.51, 1.42 Hz, 1H), 7.25 (d,J=8.51 Hz, 1H), 6.98 (d, J=8.51 Hz, 1H), 4.34-4.27 (m, 4H), 3.78 (s,2H), 2.61 (heptet, J=5.87 Hz, 1H), 2.47 (bs, 8H), 2.24 (s, 3H), 0.96 (d,J=5.87 Hz, 6H). HRMS (ESI⁺): Found [M+H]⁺ 580.2938 C₃₄H₃₈N₅O₄ requires580.2918.

The following compounds were synthesised according to the procedure forExample 202, by substituting the appropriate amine for1-isopropylpiperazine.

-   Example 203,    2-(azetidin-1-ylmethyl)-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)quinoline-6-carboxamide-   Example 204,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide-   Example 205,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((2-methylpyrrolidin-1-yl)methyl)quinoline-6-carboxamide-   Example 206,    (R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((3-fluoropyrrolidin-1-yl)methyl)quinoline-6-carboxamide-   Example 207,    (S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((3-fluoropyrrolidin-1-yl)methyl)quinoline-6-carboxamide-   Example 208,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-((3-methoxypyrrolidin-1-yl)methyl)quinoline-6-carboxamide-   Example 209,    N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(piperidin-1-ylmethyl)quinoline-6-carboxamide

TABLE H Compound 1H NMR Mass Spec Example ¹H-NMR (500 MHz, MeOD): δ 8.60(d, J = 2.03 Hz, 1H), Found [M + H]⁺ 203 8.48 (d, J = 8.14 Hz, 1H), 8.30(dd, J = 8.81, 2.03 Hz, 1H), 509.2183 8.15 (dd, J = 8.81, 1H), 7.81 (d,J = 2.03 Hz, 1H), 7.65 (d, J = C₃₀H₂₉N₄O₄ 8.14 Hz, 1H), 7.54 (d, J =8.14, 2.03 Hz, 1H), 7.49 (d, J = requires 2.03 Hz, 1H), 7.47 (dd, J =8.14, 2.03 Hz, 1H), 7.32 (d, J = 509.2183 8.14 Hz, 1H), 6.95 (d, J =8.14 Hz, 1H), 4.35-4.28 (m, 4H), 4.06 (s, 2H), 3.54 (t, J = 7.36 Hz,4H), 2.34 (s, 3H), 2.24 (q, J = 7.36 Hz, 2H). Example ¹H-NMR (500 MHz,MeOD): δ 8.59 (d, J = 1.69 Hz, 1H), Found [M + H]⁺ 204 8.48 (d, J = 8.43Hz, 1H), 8.29 (dd, J = 8.43, 1.69 Hz, 1H), 566.2845 8.19 (d, J = 9.27Hz, 1H), 7.82 (d, J = 1.69 Hz, 1H), 7.80 C₃₃H₃₆N₅O₄ (d, J = 8.43 Hz,1H), 7.53 (dd, J = 7.59, 1.69 Hz, 1H), 7.47 requires (d, J = 2.53 Hz,1H), 7.46 (dd, J = 8.43, 2.53 Hz, 1H), 7.29 566.2762 (d, J = 8.43 Hz,1H), 6.93 (d, J = 8.43 Hz, 1H), 4.33-4.26 (m, 4H), 3.89 (s, 2H), 2.58(bs, 8H), 2.46 (q, J = 7.28 Hz, 2H), 2.32 (s, 3H), 1.11 (t, J = 7.28 Hz,3H). Example ¹H-NMR (500 MHz, DMSO): δ_(H) 10.16 (s, 1H), 10.09 (s,Found [M + H]⁺ 205 1H), 8.64 (s, 1H), 8.48 (d, J = 8.81 Hz, 1H), 8.27(dd, J = 537.2539 8.81, 1.47 Hz, 1H), 8.09 (d, J = 8.81 Hz, 1H), 7.89(d, J = C₃₂H₃₃N₄O₄ 1.47 Hz, 1H), 7.72 (d, J = 8.81 Hz, 1H), 7.59 (dd, J= 8.81, requires 2.20 Hz, 1H), 7.54 (d, J = 2.20 Hz, 1H), 7.52 (dd, J =2.20, 537.2496 8.81 Hz, 1H), 7.25 (d, J = 8.81 Hz, 1H), 6.99 (d, J =8.81 Hz, 1H), 4.39-4.24 (m, 5H), 3.64 (bs, 1H), 2.93 (bs, 1H), 2.25 (s,3H), 2.03-1.94 (m, 1H), 1.76-1.63 (m, 2H), 1.49- 1.36 (m, 1H), 1.30-1.21(m, 1H), 1.15 (d, J = 5.38 Hz, 3H). Example ¹H-NMR (500 MHz, DMSO): δ10.16 (s, 1H), 10.08 (s, 1H), Found [M + H]⁺ 206 8.64 (bs, 1H), 8.50 (d,J = 8.23 Hz, 1H), 8.26 (d, J = 8.23 541.2234 Hz, 1H), 8.09 (d, J = 8.23Hz, 1H), 8.08 (d, J = 8.81 Hz, C₃₁H₃₀FN₄O₄ 1H), 7.88 (bs, 1H), 7.72 (d,J = 8.23 Hz, 1H), 7.59 (dd, J = requires 8.23, 1.50 Hz, 1H), 7.54 (d, J= 1.50 Hz, 1H), 7.51 (dd, J = 541.2246 8.23, 1.50 Hz, 1H), 7.25 (d, J =8.23 Hz, 1H), 6.99 (d, J = 8.23 Hz, 1H), 5.33-5.14 (m, 1H), 4.36-4.28(m, 4H), 3.95 (s, 2H), 2.94-2.84 (m, 2H), 2.79-2.68 (m, 1H), 2.48-2.41(m, 1H), 2.25 (s, 3H), 2.01-1.86 (m, 1H). Example ¹H-NMR (500 MHz,DMSO): δ 10.16 (s, 1H), 10.08 (s, 1H), Found [M + H]⁺ 207 8.64 (bs, 1H),8.50 (d, J = 8.23 Hz, 1H), 8.26 (d, J = 8.23 541.2236 Hz, 1H), 8.09 (d,J = 8.23 Hz, 1H), 8.08 (d, J = 8.81 Hz, C₃₁H₃₀FN₄O₄ 1H), 7.88 (bs, 1H),7.72 (d, J = 8.23 Hz, 1H), 7.59 (dd, J = requires 8.23, 1.50 Hz, 1H),7.54 (d, J = 1.50 Hz, 1H), 7.51 (dd, J = 541.2246 8.23, 1.50, Hz, 1H),7.25 (d, J = 8.23 Hz, 1H), 6.99 (d, J = 8.23 Hz, 1H), 5.33-5.14 (m, 1H),4.36-4.28 (m, 4H), 3.95 (s, 2H), 2.94-2.84 (m, 2H), 2.79-2.68 (m, 1H),2.48-2.41 (m, 1H), 2.25 (s, 3H), 2.01-1.86 (m, 1H). Example ¹H-NMR (500MHz, DMSO): δ 10.15 (s, 1H), 10.08 (s, 1H), Found [M + H]⁺ 208 8.63 (bs,1H), 8.48 (d, J = 8.84 Hz, 1H), 8.26 (dd, J = 8.84, 553.2418 1.47 Hz,1H), 8.08 (d, J = 8.84 Hz, 1H), 7.88 (bs, 1H), 7.70 C₃₂H₃₃N₄O₅ (d, J =8.84 Hz, 1H), 7.59 (dd, J = 7.37, 1.47 Hz, 1H), 7.54 requires (d J =1.47 Hz, 1H), 7.52 (dd J = 7.37, 1.47 Hz, 1H), 7.25 553.2445 (d, J =8.84 Hz, 1H), 6.99 (d, J = 8.84 Hz, 1H), 4.36-4.26 (m, 4H), 3.95-3.88(m, 3H), 3.16 (s, 3H), 2.79-2.70 (m, 1H), 2.71-2.63 (m, 1H), 2.59-2.54(m, 2H), 2.25 (s, 3H), 2.07- 1.99 (m, 1H), 1.75-1.66 (m, 1H). Example¹H-NMR (500 MHz, DMSO): δ 10.15 (s, 1H), 10.08 (s, 1H), Found [M + H]⁺209 8.63 (bs, 1H), 8.48 (d, J = 8.11 Hz, 1H), 8.26 (d, J = 8.11 537.2488Hz, 1H), 8.08 (d, J = 8.11 Hz, 1H), 7.88 (bs, 1H), 7.73 (d, J =C₃₂H₃₃N₄O₄ 8.11 Hz, 1H), 7.59 (dd, J = 8.11, 2.32 Hz, 1H), 7.54 (d J =requires 1.16 Hz, 1H), 7.51 (dd, J = 8.11, 2.32 Hz, 1H), 7.25 (d, J =537.2496 8.11 Hz, 1H), 6.98 (d, J = 8.11 Hz, 1H), 4.36-4.28 (m, 4H),3.76 (bs, 2H), 2.48-2.38 (m, 4H), 2.24 (s, 3H), 1.59- 1.49 (m, 4H),1.47-1.37 (m, 2H).

Compound 249,N-(4-iodo-3-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

Oxalyl chloride (0.37 mL, 4.23 mmol) was added dropwise to a stirredsolution of 1,4-benzodioxane-6-carboxylic acid (0.635 g, 3.52 mmol) andDMF (6.82 μL, 0.088 mmol) in dry DCM (10 mL). The reaction mixture wasstirred for 30 minutes, then concentrated in vacuo, dissolved in DCM (10mL) and concentrated in vacuo. The concentrate was dissolved in DCM (10mL) and added drop wise to a stirred solution of pyridine (0.57 mL, 7.04mmol) and 4-iodo-3-nitroaniline (0.93 g, 3.52 mmol) in DCM (10 mL).After stirring for 16 hours, the reaction mixture was concentrated invacuo. The concentrate was suspended in MeOH (30 mL) and diluted withwater (60 mL). The solid was filtered, washed with water and dried onthe high vac to afford the desired product as a pale yellow solid (1.310g, 87%). 1H-NMR (500 MHz, DMSO): δ 10.50 (s, 1H), 8.49 (d, J=2.4 Hz,1H), 8.07 (d, J=8.6 Hz, 1H), 7.80 (dd, J=8.7, 2.5 Hz, 1H), 7.62-7.43 (m,2H), 7.01 (d, J=8.4 Hz, 1H), 4.49-4.18 (m, 4H). HRMS (ESI⁺): Found[M+H]⁺ 426.9789 C₁₅H_(12l)N₂O₅ requires 426.9785.

Compound 242,N-(3-amino-4-iodophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

To a solution ofN-(4-iodo-3-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide(400 mg, 0.939 mmol) in ethanol (3 mL) and water (0.3 mL), ammoniumchloride (351 mg, 6.57 mmol) and iron powder (367 mg, 6.57 mmol) wereadded and the resulting suspension was allowed to stir at 90° C. for 16hours. The reaction mixture was allowed to cool to room temperature,filtered and the filtrate was partitioned between DCM (5 mL) and asaturated aqueous solution of sodium hydrogen carbonate (5 mL). Thelayers were separated and the aqueous layer was extracted with DCM (3×5mL). The combined organic layers were dried over magnesium sulphate,filtered and concentrated in vacuo to afford a brown solid which wastaken directly onto the next step without any further purification(0.934 g, 100%). 1H-NMR (500 MHz, DMSO): δ 9.90 (s, 1H), 7.56-7.42 (m,3H), 7.36 (d, J=2.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.74 (dd, J=8.6,2.4 Hz, 1H), 5.22 (s, 2H), 4.30 (tt, J=6.3, 3.1 Hz, 4H). HRMS (ESI⁺):Found [M+H]⁺ 397.0042 C₁₅H₁₄IN₂O₃ requires 397.0044.

Compound 243,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-iodophenyl)-2-methylquinoline-6-carboxamide

Oxalyl chloride (0.08 mL, 0.909 mmol) was added dropwise to a solutionof 2-methylquinoline-6-carboxylic acid (170 mg, 0.909 mmol) and DMF(1.466 μL, 0.019 mmol) in dry DCM (2.3 mL). The reaction mixture wasstirred for 30 minutes, then concentrated in vacuo, dissolved in DCM (5mL) and concentrated in vacuo. The concentrate was dissolved in DCM (5mL) and added drop wise to a stirred solution of pyridine (0.122 mL) andN-(3-amino-4-iodophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide(300 mg, 0.757 mmol) in DCM (2.3 mL). After stirring for 16 hours, thereaction mixture was concentrated in vacuo. The concentrate wassuspended in MeOH (10 mL) and diluted with water (60 mL). The solid wasfiltered, washed with water and dried on the high vac to afford thedesired product as a pale yellow solid (351 mg, 82%). ¹H-NMR (500 MHz,DMSO): δ 10.29 (s, 1H), 10.24 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.45-8.39(m, 1H), 8.26 (dd, J=8.8, 2.1 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.01 (d,J=2.5 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.63-7.49 (m, 4H), 4.39-4.26 (m,5H), 2.71 (s, 3H). HRMS (ESI⁺): Found [M+H]⁺ 566.0533 C₂₆H₂₁1N₃O₄requires 566.0571.

Example 210,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-vinylphenyl)-2-methylquinoline-6-carboxamide

Tetrakis(triphenylphosphine)palladium(O) (12.3 mg, 10.6 Pmol) was addedto a stirred solution of vinylboronic acid pinacol ester (27.0 μL, 0.159μmol),N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-iodophenyl)-2-methylquinoline-6-carboxamide(60 mg, 0.106 mmol) and an aqueous solution of potassium hydroxide (3 M,106 μL, 0.318 mmol) in THF (1.1 mL). After stirring for 16 hours thereaction mixture was concentrated in vacuo. Purification using a Biotage10 g snap column with 0-5% MeOH in DCM to afford the desired product asa pale yellow solid (12 mg, 24%). ¹H-NMR (500 MHz, DMSO): δ 10.33 (s,1H), 10.19 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.25(dd, J=8.8, 2.1 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.90 (d, J=1.9 Hz, 1H),7.76-7.67 (m, 2H), 7.58-7.47 (m, 3H), 6.99 (d, J=8.4 Hz, 1H), 6.87 (dd,J=17.5, 11.1 Hz, 1H), 5.78 (dd, J=17.5, 1.4 Hz, 1H), 5.24 (dd, J=11.0,1.3 Hz, 1H), 4.31 (td, J=5.3, 3.7 Hz, 4H), 2.71 (s, 3H). HRMS (ESI⁺):Found [M+H]⁺ 466.1767 C₂₈H₂₄N₃O₄ requires 466.1774.

Example 211,N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide

2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxylic acid hydrochloride(75 mg, 0.23 mmol) was suspended in thionyl chloride (2.0 mL) and heatedto 60° C. under argon for 4 h. The solvent was then removed in vacuo.The residue was re-dissolved in anhydrous DCM (2.0 mL) and the solventremoved in vacuo (×2). The acid chloride was re-suspended in anhydrousDCM (2.0 mL) and anhydrous dioxane (1.0 mL) thenN-(3-amino-4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide(78 mg, 0.26 mmol) was added, followed by triethylamine (0.16 mL, 118.0mg, 1.16 mmol). The reaction mixture was allowed to stir at RT for 16 h,after which time the solvents were removed in vacuo. The crude materialwas purified by SCX chromatography, eluting with MeOH followed by 10% 2MNH₃ in MeOH/MeOH. Further purification by column chromatography using agradient of 0 to 10% MeOH/DCM, followed by purification usingpreparative TLC (eluting with 2×5% MeOH/DCM) gave the title compound asa white solid (0.9 mg, 0.7%). ¹H NMR (500 MHz, Methanol-d₄) δ 8.54 (d,J=2.0 Hz, 1H), 8.37 (d, J=8.9 Hz, 1H), 8.27-8.24 (m, 2H), 7.96 (d, J=8.8Hz, 1H), 7.64 (dd, J=8.8, 2.5 Hz, 1H), 7.52-7.47 (m, 3H), 7.17 (d, J=8.9Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 4.35-4.29 (m, 4H), 3.73-3.67 (m, 2H),3.49-3.41 (m, 2H), 2.15-2.10 (s, 4H), 1.36-1.30 (m, 4H). HRMS (ESI⁺):calcd for C₃₁H₃₀ ³⁵ClN₄O₅(M+H)⁺, 573.1905; found 573.1880.

Example 212,(R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethyl-2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide

A solution ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-formylquinoline-6-carboxamide(0.200 g, 0.424 mmol) and (R)-tert-butyl3-methylpiperazine-1-carboxylate in dry DCM (2.00 mL) was allowed tostir at 20° C. for 12 h, after which sodium triacetoxyborohydride (0.270g, 1.273 mmol) was added in one portion and the resulting mixture wasallowed to stir at 20° C. for 2 h. The reaction was quenched with NaHCO₃saturated aqueous solution (5 mL) and extracted with a mixture DCM/MeOH9/1 (3×5 mL). The organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure to afford the crude product (R)-tert-butyl4-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)carbamoyl)quinolin-2-yl)methyl)-3-methylpiperazine-1-carboxylate,which was dissolved in dry DCM (2.5 mL) and treated with TFA (0.162 mL,2.120 mmol). The resulting mixture was allowed to stir for 18 h, afterwhich it was concentrated under vacuum to afford the crude product(R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide,which was taken directly onto the next step without any furtherpurification. To a solution of(R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide(0.185 g, 0.333 mmol) in dry methanol (3 mL) at 0° C., sodiumcyanoborohydride (23.02 mg, 0.366 mmol) was added in one portion,followed by the dropwise addition of acetaldehyde (0.013 mL, 0.233 mmol)and the resulting solution was allowed to warm to 20° C. and stir underargon for 18 h. The solvent was removed under reduced pressure and thecrude was redissolved in DCM (5 mL) and washed with NaOH aqueoussolution (1 M, 5 mL). Purification via flash column chromatography onsilica gel in gradient: DCM/MeOH from 0 to 20% followed by water washand trituration in Et₂O afforded the title compound as a white solid (27mg, 14%). ¹H-NMR (500 MHz, DMSO): δ 10.38 (s, 1H), 10.18 (s, 1H), 8.64(d, J 2.20 Hz, 1H), 8.48 (d, J=8.79 Hz, 1H), 8.24 (dd, J=8.79, 2.20 Hz,1H), 8.14 (dd, J=6.55, 2.20 Hz, 1H), 8.07 (d, J=8.79 Hz, 1H), 7.74 (d,J=8.79 Hz, 1H), 7.68-7.63 (m, 1H), 7.54 (d, J=2.20 Hz, 1H), 7.52 (d,J=8.79, 2.20 Hz, 1H), 7.29 (app t, J=10.28 Hz, 1H), 6.99 (d, J=8.79 Hz,1H), 4.35-4.28 (m, 4H), 4.23 (d, J=14.21 Hz, 1H), 3.53 (d, J=14.21 Hz,1H), 2.74-2.57 (m, 3H), 2.34-2.21 (m, 4H), 2.12-1.99 (m, 1H), 1.95-1.82(m, 1H), 1.09 (d, J=6.50 Hz, 3H), 0.98 (t, J=7.00 Hz, 3H). HRMS (ESI⁺):Found [M+H]⁺ 584.2665 C₃₃H₃₅FN₅O₄ requires 584.2668.

Example 213,(S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethyl-2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide

A solution ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-formylquinoline-6-carboxamide(0.200 g, 0.424 mmol) and (S)-tert-butyl3-methylpiperazine-1-carboxylate in dry DCM (2.00 mL) was allowed tostir at 20° C. for 12 h, after which sodium triacetoxyborohydride (0.270g, 1.273 mmol) was added in one portion and the resulting mixture wasallowed to stir at 20° C. for 2 h. The reaction was quenched with NaHCO₃saturated aqueous solution (5 mL) and extracted with a mixture DCM/MeOH9/1 (3×5 mL). The organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure to afford the crude product (S)-tert-butyl4-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)carbamoyl)quinolin-2-yl)methyl)-3-methylpiperazine-1-carboxylate,which was dissolved in dry DCM (2.5 mL) and treated with TFA (0.162 mL,2.120 mmol). The resulting mixture was allowed to stir for 18 h, afterwhich it was concentrated under vacuum to afford the crude product(S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide,which was taken directly onto the next step without any furtherpurification. To a solution of(S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide(0.185 g, 0.333 mmol) in dry methanol (3 mL) at 0° C., sodiumcyanoborohydride (23.02 mg, 0.366 mmol) was added in one portion,followed by the dropwise addition of acetaldehyde (0.013 mL, 0.233 mmol)and the resulting solution was allowed to warm to 20° C. and stir underargon for 18 h. The solvent was removed under reduced pressure and thecrude was redissolved in DCM (5 mL) and washed with NaOH aqueoussolution (1 M, 5 mL). Purification via flash column chromatography onsilica gel in gradient: DCM/MeOH from 0 to 20% followed by water washand trituration in Et₂O afforded the title compound as a white solid (60mg, 29%). ¹H-NMR (500 MHz, DMSO): δ 10.38 (s, 1H), 10.18 (s, 1H), 8.64(d, J=2.16 Hz, 1H), 8.48 (d, J=8.66 Hz, 1H), 8.24 (dd, J=8.66, 2.16 Hz,1H), 8.14 (dd, J=6.55, 2.16 Hz, 1H), 8.07 (d, J=8.66 Hz, 1H), 7.74 (d,J=8.66 Hz, 1H), 7.68-7.63 (m, 1H), 7.54 (d, J=2.16 Hz, 1H), 7.52 (d,J=8.66, 2.16 Hz, 1H), 7.29 (app t, J=10.28 Hz, 1H), 6.99 (d, J=8.66 Hz,1H), 4.34-4.22 (m, 5H), 3.61 (bs, 1H), 3.12-2.56 (m, 6H), 2.49-1.87 (m,3H), 1.13 (bs, 6H). HRMS (ESI⁺): Found [M+H]⁺ 584.2665 C₃₃H₃₅FN₅O₄requires 584.2668.

Example 214,N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(1-(4-ethylpiperazin-1-yl)ethyl)quinoline-6-carboxamide

To a solution ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-formylquinoline-6-carboxamide(0.300 g, 0.636 mmol) in dry dioxane (8 mL) and THF (4.00 mL) underargon at 20° C., MeMgBr (0.409 mL, 0.573 mmol) was added dropwise toobtain a yellow suspension which was allowed to stir for 1.5 h. Thereaction was quenched with NaHCO₃ saturated aqueous solution (10 mL) andextracted with a mixture DCM/MeOH 9/1 (3×5 mL). The crude was taken ontothe next step without purification. To a solution ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-(1-hydroxyethyl)quinoline-6-carboxamide(0.200 g, 0.410 mmol) and DMAP (5.01 mg, 0.041 mmol) in dry DCM (4 mL)at 20° C., Et₃N (0.243 mL, 4.10 mmol) was added dropwise followed by theaddition of methanesulfonic anhydride (429 mg, 2.462 mmol) in oneportion. The reaction mixture was allowed to stir at 20° C. for 2 hoursafter which it was concentrate under reduced pressure to afford thecrude product which was taken onto the next step without purification.To a solution of1-(6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)carbamoyl)quinolin-2-yl)ethylmethanesulfonate (232 mg, 0.410 mmol) in dry acetonitrile (4 mL) at 20°C., 1-ethylpiperazine (0.052 mL, 0.410 mmol) was added dropwise and theresulting mixture was allowed to stir for 20 hours. The reaction mixturewas concentrated under reduced pressure and washed with Et₂O to afford acrude product as a dark yellow solid. Flash column chromatography onsilica gel (from 0 to 15% MeOH in DCM) followed by preparative TLC(DCM/MeOH 9/1), wash in water and trituration in Et₂O afforded the pureproduct as a pale yellow solid (22 mg, 9%). ¹H-NMR (500 MHz, DMSO): δ10.46 (s, 1H), 10.26 (s, 1H), 8.68 (s, 1H), 8.48 (d, J=8.56 Hz, 1H),8.27 (dd, J=9.27, 2.14 Hz, 1H), 8.14 (dd, J=7.37, 2.14 Hz, 1H), 8.08 (d,J=8.56 Hz, 1H), 7.72 (d, J=8.56 Hz, 1H), 7.71-7.65 (m, 1H), 7.57 (d,J=2.14 Hz, 1H), 7.54 (dd, J=8.56, 2.14 Hz, 1H), 7.29 (app t, J=9.60 Hz,1H), 6.98 (d, J=8.56 Hz, 1H), 4.37-4.25 (m, 4H), 3.83-3.72 (m, 1H),2.77-2.21 (m, 10H), 1.40 (d, J=8.67 Hz, 3H), 1.00 (bs, 3H). HRMS (ESI⁺):Found [M+H]⁺ 584.2655 C₃₃H₃₅FN₅O₄ requires 584.2668.

Example 215,N-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide

A solution ofN-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-formylquinoline-6-carboxamide(0.5 g, 0.939 mmol) and 1-ethylpiperazine in dry DCM (8 mL) was allowedto stir at 20° C. for 12 h, after which sodium triacetoxyborohydride(0.597 g, 2.82 mmol) was added in one portion and the resulting mixturewas allowed to stir at 20° C. for 1 h. The reaction was quenched withNaHCO₃ saturated aqueous solution (10 mL) and extracted with a mixtureDCM/MeOH 9/1 (3×10 mL). Purification via flash column chromatography onsilica gel in gradient DCM/MeOH from 0 to 20%, followed by wash inwater, trituration in Et₂O and quick flush through SCX-2 cartridge,afforded the desired product as a bright yellow solid (110 mg, 18%).¹H-NMR (500 MHz, DMSO): δ 10.31 (s, 1H), 10.27 (s, 1H), 8.66 (d, J=2.18Hz, 1H), 8.50 (d, J=8.70 Hz, 1H), 8.27 (dd, J=8.70, 2.18 Hz, 1H),8.13-8.08 (m, 2H), 7.73 (d, J=8.70 Hz, 1H), 7.70-7.68 (m, 2H), 7.55 (d,J=2.18 Hz, 2H), 7.52 (dd, J=8.70, 2.18 Hz, 1H), 7.00 (d, J=8.70 Hz, 1H),4.35-4.28 (m, 4H), 3.81 (bs, 2H), 2.51 (bs, 10H), 1.02 (bt, J=6.68 Hz,3H). HRMS (ESI⁺): Found [M+H]⁺ 632.1662 C₃₂H₃₃BrN₅O₄ requires 632.1696.

Example 216,2-(azetidin-1-ylmethyl)-N-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide

A solution ofN-(2-bromo-5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-formylquinoline-6-carboxamide(0.5 g, 0.939 mmol) and azetidine in dry DCM (8 mL) was allowed to stirat 20° C. for 12 h, after which sodium triacetoxyborohydride (0.597 g,2.82 mmol) was added in one portion and the resulting mixture wasallowed to stir at 20° C. for 1 h. The reaction was quenched with NaHCO₃saturated aqueous solution (10 mL) and extracted with a mixture DCM/MeOH9/1 (3×10 mL). Purification via flash column chromatography on silicagel in gradient DCM/MeOH from 0 to 20%, followed by wash in water,trituration in Et₂O and quick flush through SCX-2 cartridge, affordedthe desired product as a bright yellow solid. (54 mg, 10%). ¹H-NMR (500MHz, DMSO): δ 10.33 (s, 1H), 10.27 (s, 1H), 8.67 (d, J=1.52 Hz, 1H),8.53 (d, J=7.99 Hz, 1H), 8.29 (dd, J=8.79, 1.52 Hz, 1H), 8.13-8.09 (m,2H), 7.69 (d, J=1.52 Hz, 1H), 7.65 (d, J=8.79 Hz, 2H), 7.55 (d, J=2.40Hz, 1H), 7.52 (dd, J=7.99, 1.52 Hz, 1H), 7.00 (d, J=7.99 Hz, 1H),4.35-4.28 (m, 4H) 4.19 (bs, 2H), 3.59 (bs, 4H), 2.18 (bs, 2H). HRMS(ESI⁺): Found [M+H]⁺ 575.1088 C₂₉H₂₆BrN₄O₄ requires 575.1116.

Example 217,(S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-isopropyl-2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide

A solution ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-formylquinoline-6-carboxamide(200 mg, 0.424 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate(255 mg, 1.273 mmol) in dry DCM (2.000 mL) was allowed to stir at 20° C.for 12 h, after which sodium triacetoxyborohydride (270 mg, 1.273 mmol)was added in one portion and the resulting mixture was allowed to stirat 20° C. for 2 h. The reaction was quenched with NaHCO₃ saturatedaqueous solution (5 mL) and extracted with a mixture DCM/MeOH 9/1 (3×5mL). The organic layers were dried over Na₂SO₄ and concentrated underreduced pressure to afford the crude product (S)-tert-butyl4-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)carbamoyl)quinolin-2-yl)methyl)-3-methylpiperazine-1-carboxylatewhich was dissolved in dry DCM (4 mL) and treated with TFA (0.162 mL,2.120 mmol). The resulting mixture was allowed to stir for 18 h, afterwhich it was concentrated under vacuum to afford the crude product as abeige solid, which was purified via flash column chromatography onsilica gel in gradient DCM/MeOH from 0 to 10% to afford a beige solid aspure product (157 mg, 67%). ¹H-NMR (500 MHz, MeOD): δ8.61 (d, J 1.47 Hz,1H), 8.54 (d, J=8.83 Hz, 1H), 8.32 (dd, J=8.83, 1.47 Hz, 1H), 8.22 (dd,J=6.62, 2.21 Hz, 1H), 8.17 (d, J=8.83 Hz, 1H), 7.84 (d, J=8.83 Hz, 1H),7.59-7.54 (m, 1H), 7.50 (d, J=2.21 Hz, 1H), 7.48 (d, J=8.09, 1.47 Hz,1H), 7.29 (app t, J=9.56 Hz, 1H), 6.96 (d, J=8.09 Hz, 1H), 4.45 (d,J=13.95 Hz, 1H), 4.34-4.28 (m, 4H), 3.82 (d, J=13.95 Hz, 1H), 3.36 (bs,2H), 3.23-3.16 (m, 1H), 3.07-2.94 (m, 3H), 2.76-2.67 (m, 1H), 1.30 (d,J=5.17 Hz, 3H). HRMS (ESI⁺): Found [M+H]⁺ 556.2341 C₃₁H₃₁FN₅O₄ requires556.2355. To a solution of(S)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide(150 mg, 0.270 mmol) in dry DCM (2 mL), propan-2-one (0.059 mL, 0.810mmol) and acetic acid (0.015 mL, 0.270 mmol) were added dropwise and theresulting mixture was allowed to stir at 20° C. for 6 hours, after whichsodium triacetoxyborohydride (172 mg, 0.810 mmol) was added in oneportion and the resulting mixture was allowed to stir at 20° C. for 18hours. The reaction was quenched with NaHCO₃ saturated aqueous solutionand extracted with a mixture DCM/MeOH 9/1. Purification via flash columnchromatography on silica gel in gradient DCM/MeOH from 0 to 15%,followed by quick flush through SCX-2 cartridge with MeOH and NH₃,afforded the desired product as a very pale yellow solid (40 mg, 25%).¹H-NMR (500 MHz, DMSO): δ 10.41 (s, 1H), 10.20 (s, 1H), 8.66 (d, J=1.76Hz, 1H), 8.50 (d, J=8.24 Hz, 1H), 8.26 (dd, J=8.82, 1.76 Hz, 1H), 8.15(dd, J=7.06, 1.76 Hz, 1H), 8.09 (d, J=8.82 Hz, 1H), 7.74 (d, J=8.82 Hz,1H), 7.68-7.63 (m, 1H), 7.55 (d, J=1.76 Hz, 1H), 7.52 (d, J=8.82, 1.76Hz, 1H), 7.29 (app t, J=9.41 Hz, 1H), 6.99 (d, J=8.24 Hz, 1H), 4.36-4.21(m, 5H), 3.61 (bs, 1H), 3.26-2.53 (m, 8H), 1.16 (bs, 9H). HRMS (ESI⁺):Found [M+H]⁺ 598.2805 C₃₄H₃₇FN₅O₄ requires 598.2824.

Example 218,(R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-isopropyl-2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide

A solution ofN-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-formylquinoline-6-carboxamide(200 mg, 0.424 mmol) and (R)-tert-butyl 3-methylpiperazine-1-carboxylate(255 mg, 1.273 mmol) in dry DCM (2.000 mL) was allowed to stir at 20° C.for 12 h, after which sodium triacetoxyborohydride (270 mg, 1.273 mmol)was added in one portion and the resulting mixture was allowed to stirat 20° C. for 2 h. The reaction was quenched with NaHCO₃ saturatedaqueous solution (5 mL) and extracted with a mixture DCM/MeOH 9/1 (3×5mL). The organic layers were dried over Na₂SO₄ and concentrated underreduced pressure to afford the crude product (R)-tert-butyl4-((6-((5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)carbamoyl)quinolin-2-yl)methyl)-3-methylpiperazine-1-carboxylatewhich was dissolved in dry DCM (4 mL) and treated with TFA (0.162 mL,2.120 mmol). The resulting mixture was allowed to stir for 18 h, afterwhich it was concentrated under vacuum to afford the crude product as abeige solid, which was purified via flash column chromatography onsilica gel in gradient DCM/MeOH from 0 to 10% to afford a beige solid aspure product (220 mg, 93%). ¹H-NMR (500 MHz, MeOD): b8.58 (d, J 1.49 Hz,1H), 8.51 (d, J=8.21 Hz, 1H), 8.28 (dd, J=8.96, 1.49 Hz, 1H), 8.21 (dd,J=6.72, 2.24 Hz, 1H), 8.14 (d, J=8.96 Hz, 1H), 7.82 (d, J=8.21 Hz, 1H),7.57-7.52 (m, 1H), 7.47 (d, J=2.24 Hz, 1H), 7.46 (d, J=8.21, 2.24 Hz,1H), 7.20 (app t, J=9.70 Hz, 1H), 6.92 (d, J=8.21 Hz, 1H), 4.47 (d,J=13.59 Hz, 1H), 4.33-4.26 (m, 4H), 3.86 (d, J=13.59 Hz, 1H), 3.36 (bs,2H), 3.26-3.18 (m, 1H), 3.12-2.98 (m, 3H), 2.83-2.74 (m, 1H), 1.29 (d,J=5.82 Hz, 3H). HRMS (ESI⁺): Found [M+H]⁺ 556.2343 C₃₁H₃₁FN₅O₄ requires556.2355. To a solution of(R)—N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((2-methylpiperazin-1-yl)methyl)quinoline-6-carboxamide(150 mg, 0.270 mmol) in dry DCM (2 mL), propan-2-one (0.059 mL, 0.810mmol) and acetic acid (0.015 mL, 0.270 mmol) were added dropwise and theresulting mixture was allowed to stir at 20° C. for 6 hours, after whichsodium triacetoxyborohydride (172 mg, 0.810 mmol) was added in oneportion and the resulting mixture was allowed to stir at 20° C. for 18hours. The reaction was quenched with NaHCO₃ saturated aqueous solutionand extracted with a mixture DCM/MeOH 9/1. Purification via flash columnchromatography on silica gel in gradient DCM/MeOH from 0 to 10% affordedthe desired product as a white solid (165 mg, 67%). ¹H-NMR (500 MHz,DMSO): δ 10.39 (s, 1H), 10.19 (s, 1H), 8.65 (d, J=2.04 Hz, 1H), 8.49 (d,J=8.17 Hz, 1H), 8.25 (dd, J=8.17, 2.04 Hz, 1H), 8.15 (dd, J=6.80, 2.04Hz, 1H), 8.08 (d, J=8.17 Hz, 1H), 7.74 (d, J=8.17 Hz, 1H), 7.67-7.63 (m,1H), 7.54 (d, J=2.04 Hz, 1H), 7.52 (d, J=8.17, 2.04 Hz, 1H), 7.29 (appt, J=8.85 Hz, 1H), 6.99 (d, J=8.17 Hz, 1H), 4.34-4.28 (m, 4H), 4.24 (bd,J=12.95 Hz, 1H), 3.57 (bs, 1H), 2.95-1.97 (m, 8H), 1.12 (bs, 3H), 1.01(bs, 6H). HRMS (ESI⁺): Found [M+H]⁺ 598.2794 C₃₄H₃₇FN₅O₄ requires598.2824.

Biological Activity

The exemplified compounds above were tested in the assays describedabove in the biological assay section (the Arrayscan, Cellisa and TitreBlue assays). The following data was obtained:

Example No. Arrayscan (μM) Cellisa (μM)¹ Titre Blue (μM) 1 nd 0.0050.014 2 nd 0.007 0.025 3 nd 0.007 0.029 4 nd 0.010 0.018 5 nd 0.0530.047 6 nd 0.017 0.077 7 nd 0.055 0.037 8 nd 0.205 0.108 9 nd 0.0220.090 10 nd 0.029 0.015 11 nd 0.038 0.095 12 nd 0.051 nd 13 nd 0.2620.217 14 nd 0.081 0.094 15 nd 0.076 0.075 16 nd 0.094 0.031 17 nd 0.0970.073 18 nd 0.062 0.034 19 nd 0.289 0.320 20 nd 1.477 nd 21 nd 0.1410.084 22 nd 0.160 nd 23 nd 0.161 nd 24 nd 0.174 0.169 25 nd 1.609 1.12626 nd 0.262 0.071 27 nd 0.371 0.106 28 nd 0.416 0.415 29 nd 0.499 0.62630 nd 0.507 nd 31 nd 0.545 nd 32 nd 0.665 nd 33 nd 0.797 0.230 34 nd0.850 0.413 35 nd 0.867 0.432 36 nd 1.147 0.567 37 nd 1.963 nd 38 0.0460.041 nd 39 0.082 0.008 0.023 40 nd 1.163 nd 41 nd 0.104 0.154 42 nd0.546 0.665 43 nd 0.022 0.034 44 nd 0.011 0.024 45 nd 0.036 0.085 46 nd0.004 0.012 47 nd 0.004 0.012 48 nd 0.141 0.172 49 nd 0.002 0.008 50 nd0.003 0.010 51 nd 0.004 0.010 52 nd 0.012 0.006 53 nd 0.007 0.007 54 nd0.010 0.007 55 nd 0.013 0.020 56 nd 0.013 0.003 57 nd 0.037 0.031 58 nd0.015 0.033 59 nd 0.015 0.410 60 nd 0.016 0.013 61 nd 0.016 0.018 62 nd0.017 0.016 63 nd 0.022 0.007 64 nd 0.025 0.032 65 nd 0.029 0.007 66 nd0.030 0.040 67 nd 0.035 0.033 68 nd 0.041 0.012 69 nd 0.057 0.305 70 nd0.059 0.092 71 nd 0.082 0.118 72 nd 0.105 0.060 73 nd 0.090 0.021 74 nd0.232 nd 75 nd 0.017 0.056 76 nd 0.021 0.010 77 nd 0.026 nd 78 nd 0.0450.091 79 nd 0.070 0.054 80 nd 0.070 0.032 81 nd 0.100 0.044 82 nd 0.156nd 83 nd 0.161 nd 84 nd 0.184 0.095 85 nd 1.144 nd 86 nd 0.195 nd 87 nd0.608 0.260 88 nd 0.770 nd 89 nd 0.013 0.015 90 3.919 nd 1.365 91 0.2860.070 0.115 92 4.503 4.408 3.282 93 1.598 2.460 0.798 94 0.079 0.073 950.129 0.089 0.156 96 2.625 4.445 1.349 97 0.170 0.059 0.032 98 3.0902.663 nd 99 0.214 0.042 0.062 100 0.128 0.043 0.054 101 0.425 0.1220.059 102 2.440 0.835 nd 103 0.123 0.060 0.074 104 1.693 0.482 nd 1050.896 nd nd 106 3.881 nd nd 107 0.373 0.295 0.227 108 0.545 0.483 nd 1090.482 nd nd 110 0.130 0.410 0.168 111 0.173 1.840 nd 112 1.877 nd nd 1131.036 0.160 0.117 114 0.167 0.035 nd 115 0.317 nd nd 116 1.328 nd nd 1170.077 0.635 nd 118 1.984 0.618 nd 119 0.814 nd nd 120 2.892 2.731 nd 1210.412 nd 0.338 122 0.953 nd nd 123 0.321 nd nd 124 0.066 nd nd 125 0.493nd nd 126 3.214 nd nd 127 0.647 nd nd 128 0.292 nd nd 129 0.519 0.3440.162 130 1.072 0.156 nd 131 0.237 0.171 0.074 132 nd 0.226 nd 133 nd0.127 0.111 134 nd 0.051 0.049 135 nd 0.027 0.029 136 nd 0.014 0.004 137nd 0.015 0.026 138 nd 0.031 0.010 139 nd 0.020 0.023 140 nd 0.031 0.034141 nd 0.032 0.044 142 nd 0.051 nd 143 nd 0.055 0.026 144 nd 0.060 0.080145 nd 0.064 0.017 146 nd 0.077 0.020 147 nd 0.083 0.054 148 nd 0.0880.104 149 nd 0.063 0.020 150 nd 0.098 0.086 151 nd 0.100 0.026 152 nd0.105 0.153 153 nd 0.140 nd 154 nd 0.145 nd 155 nd 0.227 nd 156 nd 0.1610.079 157 nd 0.221 nd 158 nd 0.239 0.202 159 nd 0.345 nd 160 nd 0.383 nd161 nd 0.911 0.557 162 nd 0.984 nd 163 nd 1.131 1.851 164 nd 1.545 0.859165 nd 0.005 0.001 166 nd 0.298 0.068 167 nd 0.176 0.086 168 nd 0.0140.019 169 0.056 170 0.379 171 0.45  172 0.675 173 0.1  174 0.078 1750.647 176 0.313 177 0.07  178 0.044 179 0.019 180 0.208 181 0.149 1820.232 183 0.131 184 0.06  185 0.137 186 0.013 187 0.01  188 0.057 1890.027 190 0.267 191 0.134 192 0.128 193 0.066 194 0.213 195 0.066 1960.048 197 0.043 198 0.173 199 0.085 200 0.084 201 0.083 202 0.061 2030.023 204 0.056 205 0.065 206 0.076 207 0.08  208 0.053 209 0.208 2100.419 211 0.073 212 0.085 213 0.057 214 0.957 215 0.039 216 0.055 2170.137 218 0.08  ¹Examples 1-168 were tested using U2OS cells andExamples 169-218 were tested using SK-OV-3 cells.

REFERENCES

-   1. Altenbach, R. J.; Black, L. A.; Chang, S.-j.; Cowart, M. D.;    Faghih, R.; Gfesser, G. A.; Ku, Y.-y.; Liu, H.; Lukin, K. A.;    Nersesian, D. L.; Pu, Y.-m.; Sharma, P. N.; Bennani, Y. L.    Preparation of pyrrolidine derivatives as histamine-3 receptor    ligands. US20040092521A1, 2004.-   2. Sagi, K.; Fujita, K.; Sugiki, M.; Takahashi, M.; Takehana, S.;    Tashiro, K.; Kayahara, T.; Yamanashi, M.; Fukuda, Y.; Oono, S.;    Okajima, A.; Iwata, S.; Shoji, M.; Sakurai, K., Optimization of a    coagulation factor VIIa inhibitor found in factor Xa inhibitor    library. Bioorganic & Medicinal Chemistry 2005, 13 (5), 1487-1496.-   3. Giardina, G.; Clarke, G. D.; Dondio, G.; Petrone, G.; Sbacchi,    M.; Vecchietti, V., Selective .kappa.-Opioid Agonists: Synthesis and    Structure-Activity Relationships of Piperidines Incorporating an    Oxo-Containing Acyl Group. Journal of Medicinal Chemistry 1994,    37(21), 3482-3491.-   4. Wishka, D. G.; Walker, D. P.; Yates, K. M.; Reitz, S. C.; Jia,    S.; Myers, J. K.; Olson, K. L.; Jacobsen, E. J.; Wolfe, M. L.;    Groppi, V. E.; Hanchar, A. J.; Thornburgh, B. A.; Cortes-Burgos, L.    A.; Wong, E. H. F.; Staton, B. A.; Raub, T. J.; Higdon, N. R.;    Wall, T. M.; Hurst, R. S.; Walters, R. R.; Hoffmann, W. E.; Hajos,    M.; Franklin, S.; Carey, G.; Gold, L. H.; Cook, K. K.; Sands, S. B.;    Zhao, S. X.; Soglia, J. R.; Kalgutkar, A. S.; Arneric, S. P.;    Rogers, B. N., Discovery of    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide,    an Agonist of the α7 Nicotinic Acetylcholine Receptor, for the    Potential Treatment of Cognitive Deficits in Schizophrenia:    Synthesis and Structure-Activity Relationship. Journal of Medicinal    Chemistry 2006, 49 (14), 4425-4436.-   5. Nagase, T.; Mizutani, T.; Ishikawa, S.; Sekino, E.; Sasaki, T.;    Fujimura, T.; Ito, S.; Mitobe, Y.; Miyamoto, Y.; Yoshimoto, R.;    Tanaka, T.; Ishihara, A.; Takenaga, N.; Tokita, S.; Fukami, T.;    Sato, N., Synthesis, Structure-Activity Relationships, and    Biological Profiles of a Quinazolinone Class of Histamine H3    Receptor Inverse Agonists. Journal of Medicinal Chemistry 2008, 51    (15), 4780-4789.-   6. Boys, M. L.; Bradley, M.; Delisle, R. K.; Hennings, D. D.;    Kennedy, A. L.; Marmsater, F. P.; Medina, M.; Munson, M. C.; Rast,    B.; Rizzi, J. P.; Rodriguez, M. E.; Topalov, G. T.; Zhao, Q.    Preparation of substituted    N-(1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamides as cFMS    inhibitors. WO2011079076A1, 2011.-   7. Kahraman, M.; Govek, S. P.; Nagasawa, J. Y.; Smith, N. D.    Preparation of chromen-6-ol derivatives as modulators of estrogen    receptor. WO2011156518A2, 2011.-   8. Radford, P.; Attygalle, A. B.; Meinwald, J.; Smedley, S. R.;    Eisner, T., Pyrrolidinoöxazolidine Alkaloids from Two Species of    Ladybird Beetles1. Journal of Natural Products 1997, 60 (8),    755-759.-   9. Azizi, N.; Saidi, M. R., Highly Chemoselective Addition of Amines    to Epoxides in Water. Organic Letters 2005, 7 (17), 3649-3651.-   10. Bai, H.; Bailey, S.; Bhumralkar, D. R.; Bi, F.; Guo, F.; He, M.;    Humphries, P. S.; Ling, A. L.; Lou, J.; Nukui, S.; Zhou, R.    Preparation of fused phenyl amido heterocycles for the prevention    and treatment of glucokinase-mediated diseases. WO2007122482A1,    2007.

1.-28. (canceled)
 29. A method of treating a cancer selected from thegroup consisting of ovarian cancer, skin cancer, breast cancer, lungcancer, colorectal cancer, bone cancer, or Ewing's sarcoma in a patientin need thereof, comprising administering to the patient atherapeutically effective amount of a compound represented by:

or a pharmaceutically acceptable salt thereof.
 30. The method of claim29, wherein the cancer is ovarian cancer.
 31. A method of treatingovarian cancer in a patient in need thereof, comprising administering tothe patient a therapeutically effective amount of a compound representedby:

or a pharmaceutically acceptable salt thereof.
 32. A method of treatingendometrial cancer in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound represented by:

or a pharmaceutically acceptable salt thereof.